Endogenous opiates and behavior: 2005

Review

Endogenous opiates and behavior: 2005

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8

avai lab le at www.sc iencedi rec t .com

journal homepage: www.elsev ier .com/ locate /pept ides

Richard J. Bodnar *, Gad E. Klein

Department of Psychology and Neuropsychology Doctoral Sub-Program, Queens College, City University of New York, 65-30 Kissena Blvd.,

Flushing, NY 11367, United States

a r t i c l e i n f o

Article history:

Received 17 July 2006

Accepted 19 July 2006

Published on line 12 September 2006

Keywords:

Opioids

mu Receptor

kappa Receptor

delta Receptor

Enkephalins

Endomorphins

Dynorphin

beta-Endorphin

Abbreviations:

a b s t r a c t

This paper is the 28th consecutive installment of the annual review of research concerning

the endogenous opioid system, now spanning over a quarter-century of research. It sum-

marizes papers published during 2005 that studied the behavioral effects of molecular,

pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid

agonists and opioid antagonists. The particular topics that continue to be covered include

the molecular-biochemical effects and neurochemical localization studies of endogenous

opioids and their receptors related to behavior (Section 2), and the roles of these opioid

peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4);

tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking

(Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy,

development and endocrinology (Section 9); mental illness and mood (Section 10); seizures

and neurologic disorders (Section 11); electrical-related activity, neurophysiology and

transmitter release (Section 12); general activity and locomotion (Section 13); gastrointest-

inal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respira-

tion and thermoregulation (Section 16); immunological responses (Section 17).

# 2006 Elsevier Inc. All rights reserved.

Ach, acetylcholine

ACTH, adrenocorticotrophic

hormone

AGRP, agouti gene related peptide

AMSH, alpha-melanocyte-

stimulating hormone

AS, antisense

ATP, adenosine triphosphate

BDNF, brain-derived neurotrophic

factor

BEND, beta-endorphin

BFNA, beta-funaltrexamine

BNST, bed nucleus of the stria

terminalis

Ca(2+), calcium

cAMP, cyclic adenomonophosphate

CART, cocaine and amphetamine-

regulated transcript

* Corresponding author. Tel.: +1 718 997 3543; fax: +1 178 997 3257.E-mail address: [email protected] (R.J. Bodnar).

0196-9781/$ – see front matter # 2006 Elsevier Inc. All rights reserved.doi:10.1016/j.peptides.2006.07.011

mailto:[email protected]

http://dx.doi.org/10.1016/j.peptides.2006.07.011

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83392

CB, cannabinoid

CCK, cholecystokinin

cDNA, complementary

deoxyribonucleic acid

CFA, complete Freund’s adjuvant

CGRP, calcitonin gene-related

peptide

COX, cyclooxygenase

C/P, caudate/putamen

CPP, conditioned place preference

CREB, Ca(2+)/cAMP responsive

element binding protein

CRF, corticotropin factor

CSF, cerebrospinal fluid

DA, dopamine

DADL, D-Ala(2),D-Leu(5)-enkephalin

DALDA, D-Arg-Phe-Lys-NH2

DAMGO, D-Ala(2),Nme(4),Gly-ol(5)-

enkephalin

Delt, deltorphin

DOR, delta opioid receptor gene

DPDPE, D-Pen(2),D-Pen(5)-enkephalin

DRN, dorsal raphe nucleus

DYN, dynorphin

EEG, encephalographic

Enk, enkephalin

EPSC, excitatory post-synaptic

currents

ERK, extracellular regulated signal

kinases

GI, gastrointestinal

GIRK, G-protein inwardly rectifying

K+ channel subunit

GnRH, gonadotropin-releasing

hormone

GP, globus pallidus

HIV, human immunodeficiency

virus

HR, heart rate

HVA, homovanillic acid

IPSC, inhibitory post-synaptic

currents

K(+), potassium

KO, knockout

KOR, kappa opioid receptor gene

LC, locus coeruleus

L-DOPA,

1,3,4-dihydroxyphenylalanine

Lenk, Leu-enkephalin

LH, leutinizing hormone

LI, like immunoreactivity

LiCl, lithium chloride

L-NAME, N(omega)-nitro-L-arginine

methyl ester

LTP, long-term potentiation

M3G, morphine-3-glucuronide

M6G, morphine-6-glucuronide

MAP, mean arterial pressure

MAPK, mitogen-activated protein

kinase

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3393

Menk, met-enkephalin

MOR, mu opioid receptor gene

MPOA, medial preoptic area

MPTP, 1-methyl-4-phenyl-1,2,3,6-

tetrahydropyridine

MRI, magnetic resonance imaging

mRNA, messenger ribonucleic acid

NAC, nucleus accumbens

NalBzOH, naloxone

benzoylhydrazone

NBNI, nor-binaltorphamine

NE, norepinephrine

NGF, nerve growth factor

NMDA, N-methyl-D-aspartate

NO, nitric oxide

NOR, nociceptin opioid receptor

gene

NOS, nitric oxide synthase

NPY, neuropeptide Y

NRM, nucleus raphe magnus

NSAID, non-steroidal

anti-inflammatory drug

NTI, naltrindole

NTS, nucleus tractus solitarius

OFQ/N, nociceptin

6-OHDA, 6-hydroxydopamine

OXY, oxytocin

PAG, periaqueductal gray

PBN, parabrachial nucleus

PCA, patient-controlled analgesia

PET, positron emission tomography

PKA, protein kinase A

PKC, protein kinase C

POMC, pro-opiomelanocortin

PR, progressive ratio

PVN, paraventricular nucleus

RSNA, renal sympathetic nerve

activity

RT/PCR, reverse transcription/

polymerase chain reaction

RVM, rostral ventromedial medulla

SN, substantia nigra

SON, supraoptic nucleus

SG, substantia gelatinosa

SP, substance P

SSRI, selective serotonin reuptake

inhibitor

STZ, streptozotocin

TH, tyrosine hydroxylase

THC, tetrohydrocannibinol

TMJ, temporomandibular joint

TRH, thyrotropin releasing hormone

VLM, ventrolateral medulla

VP, vasopressin

VPL, ventral posterolateral nucleus

of thalamus

VTA, ventral tegmental area

0 0 6 ) 3 3 9 1 – 3 4 7 8

Contents

p e p t i d e s 2 7 ( 23394

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3395

2. Endogenous opioids and receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3396

2.1. Molecular-biochemical effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3396

2.1.1. mu Agonists and receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3396

2.1.2. delta Agonists and receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3398

2.1.3. kappa Agonists and receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3398

2.1.4. OFQ/N and ORL-1 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3399

2.2. Neuroanatomical localization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3399




2.2.4. OFQ/N and the ORL-1 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3400

3. Pain and analgesia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3401

3.1. Pain responses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3401

3.1.1. Spinal circuits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3401

3.1.2. Supraspinal circuits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3401

3.2. Opioid analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3401




3.2.4. OFQ/N and ORL-1 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3405

3.2.5. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3405

3.3. Sex, age and genetic differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3409

3.3.1. Sex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3409

3.3.2. Aging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3410

3.3.3. Genetic differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3410

3.4. Opioid mediation of other analgesic responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3410

3.4.1. Opioid-sensitive analgesic responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3410

3.4.2. Opioid-insensitive analgesic responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3411

4. Stress and social status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3411

4.1. Stress-induced analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3412

4.2. Emotional responses in opioid-mediated behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3412

4.3. Opioid involvement in stress response regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3412

5. Tolerance and dependence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3413

5.1. Animal models in tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3413

5.1.1. Cellular effects on morphine tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3413

5.1.2. Organismic effects on morphine tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3414

5.1.3. Opioid effects on morphine tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3414

5.1.4. Peptide-transmitter effects on morphine tolerance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3414

5.1.5. Other forms of opioid tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3415

5.2. Animal models in dependence and withdrawal responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3415

5.2.1. Cellular effects on morphine dependence and withdrawal responses . . . . . . . . . . . . . . . . . . . . . . . . 3415

5.2.2. Organismic effects on morphine dependence and withdrawal responses . . . . . . . . . . . . . . . . . . . . . 3416

5.2.3. Opioid effects on morphine dependence and withdrawal responses . . . . . . . . . . . . . . . . . . . . . . . . . 3416

5.2.4. Peptide-transmitter effects on morphine dependence and withdrawal responses . . . . . . . . . . . . . . . 3416

5.2.5. Other forms of opioid dependence and withdrawal responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3417

6. Learning and memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3417

6.1. Opiates and conditioned place preferences (CPP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3417

6.1.1. Opioid CPP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3417

6.1.2. Non-opioid effects on opioid CPP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3417

6.2. Opiates and conditioned aversion paradigms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3418

6.3. Opiates and drug discrimination and spatial learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3418

6.4. Opiates and memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3419

7. Eating and drinking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3419

7.1. Opioid agonists and ingestive behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3419

7.2. Opioid antagonists and ingestive behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3419

7.3. POMC-derived peptides and ingestion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3420

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3395

8. Alcohol and drugs of abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3420

8.1. Opiates and drugs of abuse: reviews. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3420

8.2. Opiates and self-administration studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3420

8.2.1. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3420

8.2.2. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3421

8.3. Opiates and ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3422

8.3.1. Animal behavioral models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3422

8.3.2. Ethanol-induced changes in opioid systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3423

8.3.3. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3423

8.4. Opiates and THC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3423

8.4.1. Animal behavioral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3423

8.4.2. Anatomical, molecular and neurochemical studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3423

8.5. Opiates and stimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8423

8.5.1. Animal behavioral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8423

8.5.2. Anatomical, molecular and neurochemical studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3424

8.5.3. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3424

8.6. Opiates and other drug abuse classes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3424

9. Sexual activity and hormones, pregnancy, development and endocrinology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3425

9.1. Sexual activity and hormones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3425

9.2. Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3425

9.3. Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3425

9.4. Endocrinology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3426

10. Mental illness and mood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3426

10.1. Mental illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3426

10.2. Mood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3426

11. Seizures and neurologic disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3426

11.1. Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3427

11.2. Neurological disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3427

12. Electrical-related activity, neurophysiology and transmitter release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3427

12.1. mu Agonists and receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3427

12.2. delta and kappa Agonists and receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3429

12.3. ORL-1 agonists and receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3429

13. General activity and locomotion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3429

14. Gastrointestinal, renal and hepatic functions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3430

14.1. Gastric function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3430

14.2. Intestinal function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3430

14.3. Nausea and emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3431

14.4. Glucose function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3431

14.5. Renal and hepatic function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3431

15. Cardiovascular responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3431

15.1. Heart rate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3431

15.2. Cardioprotection and ischemic preconditioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3432

15.3. Blood pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3432

16. Respiration and thermoregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3433

16.1. Respiration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3433

16.2. Thermoregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3434

17. Immunological responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3434

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3435

1. Introduction

This 28th installment of the annual review of research

concerning the endogenous opioid system summarizes

published papers during 2005 that studied the behavioral

effects of molecular, pharmacological and genetic manipula-

tion of opioid peptides, opioid receptors, opioid agonists and

opioid antagonists. This review continues the excellent

tradition initiated by Drs. Abba Kastin, Gayle Olson, Richard

Olson, David Coy and Anthony Vaccarino in the reviews

spanning from 1978 through 2000. As begun in the summaries

of papers published over the past 4 years (2001–2004), two

major sections of the review have been added because of the

rapid and large expansion of the field. The first is the

molecular-biochemical effects and neurochemical localiza-

tion studies of endogenous opioids and their receptors

especially as they may eventually relate to behavior (Section

2). The second is the examination of the roles of these opioid

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83396

peptides and receptors in their most studied aspect, pain and

analgesia (Section 3). As with the previous reviews, subse-

quent sections will cover the roles of opioid peptides and

receptors in the areas of stress and social status (Section 4);

tolerance and dependence (Section 5); learning and memory

(Section 6); eating and drinking (Section 7); alcohol and drugs

of abuse (Section 8); sexual activity and hormones, pregnancy,

development and endocrinology (Section 9); mental illness

and mood (Section 10); seizures and neurologic disorders

(Section 11); electrical-related activity and neurophysiology

(Section 12); general activity and locomotion (Section 13);

gastrointestinal, renal and hepatic functions (Section 14);

cardiovascular responses (Section 15); respiration and ther-

moregulation (Section 16); immunological responses (Section

17). To accommodate these additional large sections, only

published articles are covered in this review; published

abstracts from scientific meetings are not covered, but will

be added as they are published in the scientific literature.

Given the scope of this review, a paper may be inadvertently

overlooked. If this is the case, please accept my apologies, and

send the citation and abstract to http://richard.bodnar@qc.

cuny.edu, and I will include it in the next yearly review.

2. Endogenous opioids and receptors

2.1. Molecular-biochemical effects

This sub-section will review current developments in the

molecular and biochemical characteristics of opioid peptides

and receptors by subtypes: mu agonists and receptors (Section

2.1.1), delta agonists and receptors (Section 2.1.2), kappa

agonists and receptors (Section 2.1.3), and OFQ/N and the ORL-

1 receptor (Section 2.1.4).

Reviews: A review [543] analyzes development of opioid

analogues whose conformation was restricted globally (e.g.,

cyclization of amide bond formation, disulfide and mono-

sulfide bridges) or locally (e.g., incorporation of side-chain

conformational constraints). A second review [803] examines

the roles of KO and knock-down approaches in studying opioid

receptor and G-protein interactions to examine agonist-

generated cell signaling, determine the signals generated,

alteration of the intracellular trafficking routes and determine

cellular localization of effects. A third review [1021] explores

the development of neutral antagonists that possess blocking

ability of agonists at MOR without affecting basal activity to

reduce adverse side effects. A fourth review [1137] describes

six structural motifs found in MOR, KOR, DOR and NOR in

terms of their dynamic roles in the signaling mechanism

documented for G-protein coupled receptors. A validation

study [926] using three-dimensional quantitative structure–

activity relationships based on comparative molecular field

analyses indicated that pooled sets of data of mu, delta and

kappa opioid antagonists yielded statistically significant and

highly predictive models.

2.1.1. mu Agonists and receptorsA review [171] summarizes the role of drug metabolism and

disposition concepts in M6G analog drug development, and

the uses of medicinal chemistry and drug metabolism in

enhancing pharmaceutical properties and bioavailability of

M6G. A second review [816] indicates that the anti-opioid

actions of CCK and NPFF act through a cellular mechanism,

whereas the anti-opioid actions of DYN and OFQ/N act

through a circuitry-induced mechanism. A third review

[530] summarizes evidence as to how individual sensitivity

to opiates can be predicted by gene analyses. A fourth

review [907] describes the diversity and complexity of the

MOR gene by indicating alternative premRNA splicing and

promoters.

Six new splice variants of the human MOR were identified

with all variants containing exons 1–3, but differing in splices

downstream from exon 3 [906]. Five novel splice variants of

exon 5 of the MOR gene were identified with functional

consequences of C-terminal splicing described [908]. Allelic

expression imbalance of human MOR is caused by a single

nucleotide polymorphism, A118G [1367]. The 30 untranslated

region of MOR-1 mRNA was characterized in Northern blot

analyses [529]. Morphine and DAMGO promoted rapid, beta-

arrestin-dependent endocytosis of MOR in striatal neurons

[461]. Heterodimerization of MOR and DOR only occurs at the

cell surface, and requires interactions with G-proteins [664].

Activation of MOR phosphorylates IkappaB kinase and p65 in

SH-SY5Y cells [709]. A large fragment of MOR, termed TN2–3,

can be identified by CD spectroscopy in lysophosphatidylcho-

line micelles that adopts about 50% of the alpha-helical

structure [586]. MOR endocytosis is regulated by phosphoryla-

tion of the Rab5 effector, EEA1, by p38 MAP kinase [740]. MOR

endocytosis was induced by abdominal laparotomy, NMDA

treatment or electrical stimulation, but was prevented by

NMDA, but not AMPA receptor antagonists [918]. Opioid

peptide release induces MOR internalization in spinal cord

that is inhibited by NMDA receptors and large conductance

Ca2+-sensitive K+ channels [1114]. An immobilized wild-type

MOR that received the N-terminus and first transmembrane

helix of KOR to produce the receptor chimera KKM was a

hybrid that behaved exactly as a wild-type MOR in functional

assays [893]. A negative regulatory element, the Sp binding

sequence, is located in the 219–189 base pair region of the

proximal promoter of MOR [217]. All three opioid receptors

have a similar affinity to form homo- or hetero-oligomers in

combination with any other opioid, but not muscarinic M2

receptors [1252]. Cross-linking of Lys233 and Cys235 in MOR

was accomplished using a reporter affinity label [1365].

Heterodimerization of NOR and MOR impairs the ability of

DAMGO to inhibit adenylate cyclase and stimulate MAPK

phosphorylation [1254]. Whereas DAMGO stimulates ERK

through calmodulin and PKC-epsilon, the kappa agonist,

U69593, acts through phosphoinosositide 3-kinase, PKC-zeta

and Ca2+ mobilization [79]. Both single and repeated nalme-

fene treatments increased occupancy of MOR that could

persist for over 1 day [534]. Human neuroblastoma cells

synthesize morphine through mechanisms involving (S)-

[1,3,4-2H3]norlaudanosoline and [7-2H]salutaridinol [113].

Morphine and diamorphine were preserved in an intrasite

gel mixture with no clear degradation over 28 days [1355].

Arachidonic acid inhibits ligand binding to MOR and mus-

carinic, but not nicotinic Ach receptors [117]. Tilidine and

nortilidine inhibit cAMP accumulation in CHO-K1 cells

expressing MOR, and the agonist effects of DAMGO and

http://[email protected]/

http://[email protected]/

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3397

nortilidine were reversed by naloxone with very similar IC-50

values. Tilidine and nortilidine had no agonist effects on DOR,

KOR or NOR [1183]. A SAR and biological evaluation were

conducted on novel trans-3,4-dimethyl-4-arylpiperidine deri-

vatives as opioid antagonists [287]. Protein regulators of G-

protein signaling accelerate the hydrolysis of GalphaGTP to

terminate signaling at effectors and thereby restrict the

amplitude of opioid effects. The efficient deactivation of

GalphazGTP subunits by RGS-Rz proteins prevents mu

receptor desensitization [397]. Whereas acute buprenorphine

down-regulated MOR, the addition of clorazepate reduced the

level of MOR down-regulation in the hippocampus, hypotha-

lamus and thalamus [271]. The 26-base pair-polypyrimidine

stretch of the MOR proximal promoter interacts with four

members of the poly(C)binding protein family [596], and

regulates MOR gene expression [609]. A major species of

mouse MOR mRNA was identified for its promoter-dependent

functional polyadenylation signal [1301]. MOR binding is

observed in the central part of the rat sinoatrial node [1138].

MOR activation phosphorylates the STAT5 signal transducers

and activators of transcription factors that are also activated

by G-protein-coupled receptors [784]. Morphine increased

central serine racemase and D-amino acid oxidase mRNA

[1327]. NPFF and MOR couple to the carboxy termini of the

alpha-ii, alpha-i2, alpha-i3 and alpha-o subunits of the G-

protein receptors, whereas preincubation with a NPFF analo-

gue reduces the Delt-1-induced increases of carbachol-

induced release of Ca2+ from SH-SY5Y neuroblastoma cells

[815]. Coupling a benzoyl group to 6-alpha-naloxamine greatly

enhanced its MOR affinity [1317]. Compounds with 4,5-oxygen

bridge-opened 6-cyano-substituted N-methylmorphinans

were synthesized and were potent mu agonists [1120]. Chronic

morphine treatment produced up-regulation of Galpha-i2 and

cytoskeletal proteins in MOR-expressing Chinese hamster

ovary cells [1312]. MOR KO mice had lower NPY mRNA levels in

C/P and NAC and lower SP mRNA levels in the ventromedial

hypothalamus [1325]. Repeated administration of a tropane

analogue, WF-23, failed to alter mu opioid-stimulated

[35S]GTPgammaS binding, but reduced this response elicited

by agonists at D2, 5-HT-1A and alpha-2-adrenergic receptors

in the stiratum, hippocampus and amygdala respectively

[869]. Ramelteon binds to melatonin MT1 and MT2 receptors,

but has no affinity for opioid, DA or benzodiazepine receptors

[576].

A number of cyclic analogs containing para-substituted

phenylalane derivatives in place of Tyr-1 were found to be

potent mu and delta agonists in the mouse vas deferens and

guinea pig ileum assays [1277]. The novel peripheral mu opiate

antagonist, alvimopan displayed dissociation rates at the MOR

comparable to that of buprenorphine, but slower than

naloxone [172]. The potency of the MOR agonist,

[Dmt(1)]DALDA, can be changed by insertion of fluorescent

probes, particularly at the C-terminus [1045]. A H-Dmt-NH-

CH(3) opioid peptide compound produced the highest affinity

equal to that of morphine and was active in both in vitro and in

vivo assays [375]. A single dimeric opioid ligand containing the

Dmt-Tic pharmacophore exhibited highly potent MOR and

DOR antagonist activities [687]. Constricted analogues of the

N-terminal tetrapeptide, H-Tyr-D-Ala-Phe-Gly-NH2, the mini-

mal subunit for dermorphin, were synthesized [58].

Two binding sites for [125I]-labeled endomorphin-2 were

identified in the MCF7 breast cancer cell line, one with high

affinity and low capacity, and the second with low affinity and

high capacity [355]. Whereas dimerization of endomorphin-2

resulted in balanced agonists with potent analgesic activity,

modification at the C-terminal of endomorphin-2 increased its

selectivity at MOR [394]; the latter point is critical as a

conformational requirement of endomorphin-2 binding to the

MOR [531]. Tyrosine analogues of endomorphin-2 produce

potent MOR ligands [688]. Analogues with N–O turns help

develop potent analgesics related to endomorphin-2 [1274].

Interacting aromatic–aromatic and praline–aromatic pairs are

important in the stabilization of endomorphin-1 and endo-

morphin-2 [676]. Endomorphin I and II display weak antago-

nist properties upon tachykinin NK-1 receptors [625].

Endomorphin, BEND and Menk are found in CSF neurons in

the amphibian Xenopus laevis [149].

Although melatonin receptor agonists or antagonists do

not compete with opioid receptor subtypes, melatonin

produces a time-dependent release of BEND from mouse

pituitary cells in culture [1065]. Glycopeptides related to BEND

adopt helical amphipathic confirmations in the presence of

lipid bilayers [286]. BEND (1–31) and BEND (1–26) were

respectively increased 7-fold and decreased 10-fold in pitui-

tary of Cpe (fat/fat) mice that possess an inactive carbox-

ypeptidase E gene [189]. Melanocortin receptors are expressed

in bone cells such that POMC fragments increase proliferation

and expression of genes in osteoblastic cells [1374]. Mutants of

insulin degrading enzyme produce additional cleaving sites

for BEND at Lys(19)-Asn(20) and at Met(5)-Thr(6) [1115]. Plasma

BEND and Menk levels are low during sedation in ICU patients

with sufentanil, and midazolam increases these levels.

Withdrawal symptom intensities are negatively correlated

with BEND and Menk levels [622]. Chai Hu, a major ingredient

in traditional Chinese medicines, increased plasma BEND, but

decreased catecholamines [198]. Human scalp hair follicle

melanocytes synthesize and process POMC [578]. A review

[301] examines the evolution of BEND and other POMC gene

fragments in gnathostomes as compared to the agnathan

vertebrate, the marine lamprey. Structures for the POMC

family genes of proopiocortin and promelanotropin in the sea

lamprey are described [1148]. The proopiocortin gene appears

to lack essential elements for expression in the AtT-20/D16v

cells of the sea lamprey [1149].

A carbon glycoside analogue of M6G bound with less

selectivity to MOR [739]. Methadone increases intracellular

calcium in SH-SY5Y and SH-EP1-halpha7 cells by activating

neuronal nicotinic Ach receptors [903]. Probenecid decreased

the systemic elimination of M6G, but failed to affect its blood

brain barrier transport [1204]. The metabolic pathways of

buprenorphine, a synthetic derivative of the morphine

alkaloid thebaine, revealed production of the metabolite

Nor-BUP [934]. An assay has been developed and validated

for the determination of morphine, M3G and M6G in serum

[278]. Plasma MSG was not detected following oral or

intravenous administration of morphine at 25 ng/ml in dogs

[640]. A motif containing a 4-amino-1,2,4,5-tetrahydro-2-

benzazepine-3-one skeleton as a substitute for the Tic residue

has been used to develop mu antagonists [1219]. A series

of naltrexone prodrugs have been developed that convert

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83398

to naltrexone for in vitro and in vivo tests [1216]. The steady-

state plasma concentrations of ACE-naltrexone and PROP-

naltrexone were similar and effective for transdermal long-

lasting activity and delivery of the antagonist in guinea pigs

[1215].

2.1.2. delta Agonists and receptorsCo-expression of DOR produces small effects on endocytic

trafficking of the beta2-adrenergic receptor traversing a

similar membrane pathway as recycling-defective mutant

beta2-adrenergic receptors [155]. The mouse DOR gene is

regulated by DNA methylation-related chromaffin modifica-

tion especially histone acetylation and deacetylation [1253].

Whereas opioid receptor function can be eliminated by fusion

of the receptors to a G-i-alpha subunit fraction, reconstitution

of the DOR receptor was better than MOR or KOR by using two

intact receptors [913]. Bradykinin rapidly increases DOR

agonist inhibition of evoked CGRP release and cAMP accu-

mulation by increasing DOR accumulation in the plasma

membrane through a PKC-dependent mechanism [921].

Morphine promotes phosphorylation of the human DOR at

serine 363 [848]. Expression by a minigene of the third

intracellular loop of DOR inhibits signalin by opioid receptors

and other G-protein-coupled receptors [825]. beta-Arrestin-1

and beta-arrestin-2 are differentially required for phosphor-

ylation-dependent and independent internalization of DOR

[1361]. A murine DOR was engineered to contain a FLAG

epitope at the amino-terminus and a hexahistidine tag at the

carboxy terminus to facilitate purification [219]. DOR and KOR

mRNA was detected in skin fibroblast-like and mononuclear

cells [1029]. The inverse agonist, ICI174864 induces rapid

regulation in human DOR signaling efficacy using

[(35)S]GTPgammaS binding [937]. A bivalent ligand termed

KDAN-18(2) bridges phenotypic DOR-2 and KOR-1 opioid

receptors [256]. The organization of DOR and KOR as

heterodimers gives rise to delta-1 and kappa-2 phenotypes

[1310]. The seventh transmembrane domains of DOR and KOR

have different accessibility patterns and interhelical interac-

tions [1313]. A reaction product, 10-benzyl-50-hydroxyindolo-

morphinans(7) is a potent DOR antagonist [1069]. Two

indolizidine alkaloids from the Australian rainforest tree,

Elaeocarpus grandis (grandisine A and B) show affinity for

human DOR [164]. A lanthanide-based assay has proved useful

for detection of receptor–ligand interactions at DOR [470]. A

novel modeling approach using conformationally sampled

pharmacophore has been used for development DOR efficacy

[87].

Menk and Lenk can be monitored in the striatum by liquid

chromatography and electrospray ionization quadrapole ion

trap mass spectrometry in anesthetized and free-moving rats

[69]. Menk and Lenk dimers coexist with a monomer

confirmation, preferring the 5! 2 beta-turn secondary struc-

ture under the membrane-mimetic environment [148]. Pro-

Enk mRNA levels in the striatum were higher in humans with

the Val(108/158) polymorphism of the catechol-O-methyl-

transferase gene [90]. A pro-Enk precursor, containing five

Menk sequences and two extended Menk sequences has been

cloned from the amphibian, Taricha granulosa [1248]. The

heptapeptide Menk-Gly-Tyr, demonstrates one binding site in

both zebrafish and rat membranes with a majority, but not all

of the sites sensitive to naloxone displacement [422]. Capillary

liquid chromatography and tandem mass spectrometry has

been used for the quantification of Enk in CSF [1094]. Capillary

zone electrophoresis separated Enk and dalagin analogues

[1113]. DOR agonists increase E2F1 DNA binding activity and

higher levels of E2F1 DNA in NG108-15 cells [1175]. Delt II was

found to be a fully functional agonist of the mu-delta

heteromer, inducing desensitization and inhibiting adenylyl

cyclase through a pertussis-toxin-insensitive G-protein (Gal-

pha(z)) [335]. Picomole doses of DAL increase NGF in NG-108

cells while also inducing c-Jun and c-Fos [1200]. Delt II

increased [(35)S]GTPgammaS binding in a NTI-sensitive

manner with strongest effects in the striatum, NAC, olfactory

tubercule and cerebral cortex and weaker effects in the

brainstem and spinal cord [949]. The cellular uptake of Delt

and DPDPE were slowed in human nephrons containing the

A516C and A404T variants of the SLCO1A2 [670]. Substitution

of D-Arg in position 2 with Tic and masking of the lysine amide

side chain by Z protection changes the mu agonist,

[Dmt(1)]DALDA into a potent delta antagonist [54]. Further,

the potent delta agonist, H-Dmt-Tic-NH-CH(2)-bid can be

changed into a potent delta antagonist by N(1)-benzimidazole

alkylation(1) [55]. A non-peptidergic DOR agonist,

(+)BW373U86, was more potent and efficacious in increasing

[(35)S]GTPgammaS binding that was sensitive to NTI inhibi-

tion than the delta-1 peptide agonist, DPDPE [561]. The DOR

ligands, TICP and ICI174864 acted as inverse agonists in the

cyclase pathway, but induced agonist responses in the ERK

cascade [43]. [Aladan3]TIPP was developed as a fluorescent

DOR antagonist with high binding and selectivity profiles [195].

Bicyclo[2,3]-Leu-enkephalin analogues were synthesized that

retain DOR binding affinities and bioassay responses [451].

Menk and pro-Enk were decreased in mouse brains lacking

prohormone convertase-1; POMC levels were largely

unchanged [905].

2.1.3. kappa Agonists and receptorsA review [231] summarizes the selectivity of butorphanol at

the kappa receptor in terms of tolerance and cross-tolerance,

dependence and compensatory alterations in brain opioid

receptor–effector systems. A second review [304] summarizes

the potent analgesic properties of the kappa agonist, brema-

zocine as well as its perceptual and cognitive side effects. A

third review [800] presents the chemical, structure–activity

and pharmacological properties on nonpeptide KOR antago-

nists.

A full-length cDNA encoding and expressing KOR in the

rough-skinned newt, Taricha granulosa has high affinity for

U69593, DYN, U50488H and BRL52537 [128]. A mu/kappa

chimera with an extracellular loop 2 derived from KOR acted in

pharmacological profiles as if it were a MOR with high affinity

for DYN A analogs [277]. Reductions in KOR were observed in

fibroblast-like synoviocytes of patients with osteoarthritis and

rheumatoid arthritis; U65593 was less potent in enhancing

KOR mRNA expression in rheumatoid arthritis cultures [1070].

Cultures of hippocampal granule cells can be made that

express DYN mRNA among other neuromodulators [417].

Salvinorin A, TRK-820 and 3FLB displayed high affinity for KOR

over MOR, DOR and NOR on the [(35)S]GTPgammaS assay, and

caused internalization of human KOR in a dose-dependent

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3399

manner [1264]. Unique residues within a commonly shared

binding pocket are the molecular mechanism by which

salvinorin A binds and activates KOR [1316]. The pharmaco-

kinetics of salvinorin A in rhesus monkeys is subject to sex

differences [1048]. Seven pro-DYN mRNAs were identified in

the human brain with two, FL1 and FL2 encoding the full-

length pro-DYN. Whereas the FL-1 transcript is strongly

encoded in limbic structures like the NAC and amygdala,

the FL-2 transcript is weakly encoded in claustrum and

hypothalamus [861]. A cyclic DYN A analogue, [N(alpha)-

benzylTyr(1),cyclo(D-Asp(5),Dap(8))]DYN A(1–11)NH2 in the

address domain is a potent KOR antagonist [919]. kappa

Receptor agonists with high affinity were designed using the

pentapeptide Tyr-C, D-Cys-Phe-Phe and then either the D- or L-

isomers of Cys or Pen [956]. DYN A and big DYN can penetrate

into neurons by associating with the endoplasmic reticulum,

but not with Golgi apparatus or clathrin-coated endocytotic

vesicles, effects not mediated by KOR [767]. DYN A(1–11)-NH2

analogs incorporating sulphydryl-containing amino acids, L-

and D-Cys and L- and D-Pen in positions 5 and 11 produced

potent and selective actions at KOR [734]. The methyl ester and

furan rings, but not the lactone and ketone functionalities,

were required for the KOR-selective actions of Salvinoran A

[834]. Salvinorin A derivatives modified at the C2 position were

seven-fold more potent as a KOR agonist than the parent

compound [668]. MCL-145, a novel bivalent morphinan

possesses both kappa agonist and mu antagonist properties

[777]. The analogue, [NMePhe(1)]arodyn was identified as a

novel acetylated KOR antagonist [86]. A series of 3-substituted

analogues of a parent kappa agonist, designed to limit access

to the CNS by replacing the aryl acetamide portion with

substituted amino acid conjugates possessed high affinity for

KOR with apparent selectivity relative to other opiate

receptors [642]. The N-substituted cis-4a-(3hydroxyphenyl)-

8a-methyloctahydroisoqinolines series are opioid pure

antagonists with affinity at KOR [165]. kappa Agonists were

synthesized from chroman-2 carboxamide and 2,3-dihydro-

benzofuran-2-carboximide derivatives [220]. Residues 3 and 4

can be used in the cyclic tetrapeptide ligand recognition by

KOR [955].

2.1.4. OFQ/N and ORL-1 receptorA review [933] summarizes site-directed mutagenesis studies

of the NOR concentrating on transmembrane domain residues

related to changes in binding and functional activation. A

second review [150] summarizes the effectiveness of UFP-101

as a selective NOR antagonist. A third review [1351] provides a

ligand-based analysis of structural factors influencing intrin-

sic activity ast NOR. The NOR has been cloned, pharmacolo-

gically characterized and detected in brain, spinal cord and

lung of an amphibian, the rough-skinned newt Taricha

granulosa [1247]. Modifications of N- and C-terminal of OFQ/

N produced highly potent NOR ligands, particularly chemical

modification of Arg(14)-Lys(15) and (pF)Phe(4) increasing

ligand affinity and potency [454]. The NOR ligand, Ac-

RYYRWK-NH2 acted as a potent partial agonist and the whole

indole moiety of the Trp5 side chain is not required [160]. OFQ/

N derivatives were synthesized using diethylenetriaminepen-

taacetic acid as a chelator [693]. Changing Phe(4) of OFQ/N to

(pF)Phe(4) produced enhanced agonist activity, whereas

changing Ala(7), Ala(11) of OFQ/N to Aib(7), Aib(11) produced

a potent antagonist in the mouse vas deferens assay [184].

OFQ/N binding to NOR activates PKC which increases the

ability of G-protein-coupled receptor kinase 2 to phosphor-

ylate agonist-occupied MOR, thereby heterologously regulat-

ing homologous MOR desensitization [898]. NOR in the DRN is

up-regulated by previous destruction of serotonergic neurons

by 5,7-DHT [677]. A series of 3-phenoxypropyl piperidine

analogues were synthesized into NOR receptor agonists [904].

Paracetamol failed to compete for NOR receptor binding in

mouse brain and spinal cord [413]. OFQ/N displays a stable

helix conformation from residues 4–17 with functionally

important N-terminal residues being folded aperiodically on

top of the helix [886]. A series of indolin-2-ones with a

spirocyclic piperidine ring formed NOR ligands [101]. The

analogue, [Leu(11, 15)]-OFQ/N is less active than OFQ/N-amide

using pharmacological and biochemical assays [1158]. Mor-

phine induces overexpression of preproOFQ/N in cultured

astrocytes, but not neurons or microglia, an effect blocked by

naloxone, wortmannin and a MEK inhibitor [1151]. In co-

expression with NOR, MOR, DOR or KOR by transfecting dual-

expression plasmids into COS-7 cells, a full-length GAIP/RGS19

was more effective than its N-terminally truncated variant

[1307].

2.2. Neuroanatomical localization

This sub-section will review current neuroanatomical studies

indicating localization of opioid peptides and receptors by

subtypes: mu agonists and receptors (Section 2.2.1), delta

agonists and receptors (Section 2.2.2), kappa agonists and

receptors (Section 2.2.3), and OFQ/N and ORL-1 receptor

(Section 2.2.4).

2.2.1. mu Agonists and receptorsThe pan-opioid antagonist, LY2555582, displays high levels of

autoradiographic binding in the NAC, C/P, habenula, baso-

lateral amygdala, hypothalamus, thalamus and VTA, effects

that are absent in mice with combinatorial mu, delta and

kappa KO [384]. MOR mRNA was expressed in the preoptic,

area, BNST and thalamic PVN as well as the anterior, SON,

PVN, ventromedial, dorsomedial and arcuate hypothalamic

nuclei of guinea pigs with expression in subpopulations of

GnRH, DA and BEND neurons [1373]. Different types of DRG

neurons express different subpopulations of opiate receptors:

MOR alone (types 1 and 9); MOR and DOR (type 2); MOR and

KOR (types 5 and 8); MOR, DOR and KOR (types 4, 6 and 7) [973].

GABAergic neurons express MOR in the ventrolateral orbital

cortex in rats [520]. Morphine decreases the stability of

dendritic spines, effects absent in mu antagonist-treated or

MOR KO animals [692]. Morphine administered into the

substantia innominata of the basal forebrain inhibits Ach

release in the rat prefrontal cortex [890]. Acute morphine

increases DA levels in the lateral septum by decreasing

GABAergic tone in the VTA [1118]. MOR is found in the

dendritic targets of endomorphin-2 axon terminals in the NTS

[1083]. MOR mRNA and protein are expressed on Ach

interneurons in the limbic-prefrontal territory, but not in

the sensori-motor dorsal striatum with greater increases in

expression and potassium-evoked Ach by mu agonists in the

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83400

afternoon than in the morning [537]. Transgenic mice

expressing NGF in oligodendrocytes display ectopic fibers in

the white matter of the spinal cord that express MOR and

endomorphin-2 at a later post-natal period than SP; endo-

morphin-2 makes a delayed appearance in the superficial

dorsal horn [302]. A PKC-enhanced protein phosphatase

inhibitor, KEPI that is up-regulated by morphine in the

striatum is localized to the striatum, NAC, septum, BNST,

hippocampus, paraventricular thalamus, ventromedial

hypothalamus, interpeduncular nucleus, DRN and dorsal

horn of the spinal cord [421].

Striatal administration of BEND revealed BEND-IR cell

bodies in the GP and BNST with GP cell bodies co-localized

with MOR [503]. A sub-population (20–30%) of hypothalamic

arcuate neurons that contain progesterone receptors, BEND

and DYN-B projects toward the pre-optic region in ewes [310].

Vesicular glutamate transporter-2 immunoreactive neurons

contain BEND, and also make asymmetric synapses with

BEND cells in the arcuate nucleus [601]. BEND immunoreac-

tivity in the medial part of the hypothalamic arcuate nucleus

of jerboas, a long-tailed rodent species, was significantly

higher (200%) in autumn as compared to spring-summer [321].

BEND and urocortin-2 were both localized to cells in the

anterior and intermediate lobes of the pituitary gland [1315].

Astrocytes that rapidly take up circulating molecules in the

median eminence and arcuate nucleus do not contain BEND

[208]. POMC-alpha, but not POMC-beta has well-conserved

BEND segments in teleost fish. Whereas POMC-alpha is found

in the nucleus lateralis tuberis of the hypothalamus as well as

the pars distalis and intermedia of the pituitary, POMC-beta is

found in the pre-optic region [284]. Opioid growth factor and

its receptor reside on the outer nuclear envelope of the rat

tongue epithelium [1338]. Pituitary adenylate cyclase-activat-

ing polypeptide was immunohistochemically localized in the

neurohypophysis of a teleost [781] in close apposition with the

N-terminal peptide region of POMC and N-acetyl endorphin

[780].

2.2.2. delta Agonists and receptorsDOR-immunoreactive neurons were localized to the trigem-

inal, jugular and petrosal, but not nodose cranial sensory

ganglia in rats [528]. Lenk-immunoreactive neurons in the

myenteric plexus of the human gut displayed a stubby

morphological appearance with small somata, short, stubby

dendrites and one axon in which half ran orally and one-

quarter ran anally [132]. Enk-immunoreactive neurons in the

preganglionic neurons regulating the pelvic viscera were

slightly elevated in animals with spinal transecvtions 2 weeks

earlier [720]. The density of Enk-positive fibers in the GP was

decreased after quinolinate-induced excitotoxicity induced

on the seventh post-natal day [931]. More neurons projecting

from the PVN to the LC are immunoreactive for CRF (30%)

relative to Enk (2%) [986]. SP, but not Enk was not co-localized

with CART, particularly in the rostral pole of the NAC [517].

Enk was co-localized to a greater degree with either CRF or

arginine VP in the PVN of male relative to female sheep; there

was a greater degree of Enk-CRF co-localization in intact

relative to gonadectomized animals [999]. Enk-positive cells in

the murine embryonic dorsal horn expressed the NMDA NR2B

subunit more frequently than Enk-negative cells in the same

region [378]. Menk, VIP, SP and CGRP were localized on Merkel

cells of rat sinus hair follicles, and their respective receptors

were localized on Merkel cell membranes, suggestive of an

autocrine mechanism [1144]. DOR immunoreactivity was

localized in SP-positive central terminals and peripheral

elements in the chicken dorsal horn, whereas MOR immu-

noreactivity was localized in only peripheral vesicle-contain-

ing dendrites of the synaptic glomeruli [581]. Bilateral cortical

stimulation produced enhanced striatal immediate early gene

induction in both Enk-positive and Enk-negative neurons

[808]. Electron microscopy of rats with adjuvant arthritis

revealed increased Lenk in the matrix of the sciatic nerve, in

nerve fibers of the synovial membrane and periosteum as well

as in fibroblasts and endothelial cells of the periosteum, but

decreased Lenk in macrophage cells of the synovial mem-

brane and monocyte and polymorphonuclear lineage cells in

the bone marrow [1300]. Fluoxetine decreased pro-Enk gene

expression in the NAC shell and C/P, pro-DYN gene expression

in the NAC core and shell, C/P, SON and PVN, and POMC

gene expression in the arcuate nucleus [876]. The iris and

anterior ciliary body of the rat eye displayed weak immu-

nostaining of Menk and Lenk and not of OFQ/N or endomor-

phin-1 or -2 [1054]. Enk immunoreactivity was localized in the

striatum and amygdala of the fire-bellied toad, Bombina

orientalis [829]. Enk failed to display any striatal or NAC

compartmentalization in histochemical analysis of the lesser

hedgehog tenrec [643]. DOR, but not MOR nerve terminals

contact the genioglossal hypoglossal muscle motoneurons of

the cat [994].

2.2.3. kappa Agonists and receptorsKOR was expressed in the molecular and granular layers in all

lobules of the cerebellar cortex using RT/PCR and in situ

hybridization [491]. PET imaging with KOR agonist, 11C-

GR103545 in baboon brain indicated high levels of KOR in

the prefrontal cortex, cingulate cortex and striatum [1153].

Neurons expressing both pre-pro-DYN and DYN-A immunor-

eactivity were observed in the ovine supraoptic, paraventrci-

ular, preoptic, anterior, dorsomedial and arcuate

hypothalamic nuclei as well as the BNST; the ventromedial

hypothalamus only contained pre-pro-DYN [364]. A low

expression level of DYN was found in melanin-concentrating

hormone and orexin hypothalamic neurons [475]. DYN

immunoreactivity was absent in the hippocampal mole-

cular layer of two patients with hippocampal malformations

[1056].

2.2.4. OFQ/N and the ORL-1 receptorTriple KO mice deficient in MOR, DOR and KOR show absent

[3H]-NalBzOH labeling in autoradiographically determined

brain sites at low (4 nM) concentrations, but show typical

[3H]-NalBzOH labeling in known NOR brain sites at higher

(50 nM) concentrations [239]. NOR co-exists with cholinergic,

but not GABA neurons in the hippocampus, and both

hippocampal Ach and hippocampal theta rhythm were

increased in NOR KO mice [1210]. CART and OFQ/N are co-

localized in the PVN, lateral hypothalamus, zona incerta and

arcuate nucleus, whereas AGRP neurons in the arcuate

express NOR. OFQ/N decreases CART and increases AGRP in

hypothalamic explants [91].

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3401

3. Pain and analgesia

This section has four major parts examining recent advances

in: (a) pain responses especially as they may relate to opioid

function, (b) opioid analgesia organized as a function of

receptor subtypes, (c) sex, age and genetic differences in opioid

analgesic responses, and (d) opioid mediation of other

analgesic responses.

3.1. Pain responses

The following sub-sections examine work done on spinal

(Section 3.1.1) and supraspinal (Section 3.1.2) circuits, respec-

tively.

3.1.1. Spinal circuitsA review [1027] indicates that the paradoxical pro-nocicptive

effect of intrathecal morphine involves presynaptic release of

SP, glutamate and DYN in the dorsal horn, interactions with

tachykinin NK1 and NMDA receptor at multiples sites in the

dorsal horn, involvement of spinal NO systems, and the

production of M3G. A model of rodent burn injury was

produced by immersing an anesthetized rat’s paw in a 85 8C

bath for up to 12 s which resulted in mechanical allodynia and

thermal hyperalgesia accompanied by up-regulation of PKC

gamma and a progressive down-regulation of dorsal horn

MOR. Burn-injured rats showed comparable potencies for

morphine analgesia after 7 days, but a progressive rightward

shift of the morphine dose–response curve after 2 weeks

[1259]. Casein kinase 2 regulates nociceptive signaling in the

CFA and formalin pain models with all three subunits (alpha,

alpha0 and beta) expressed in spinal cord tissue [690]. A

laminectomy at the L5–L6 vertebra with extradural kaolin

administration in rats produced progressive pain develop-

ment with cauda equine clumping related to pain severity.

Both systemic and intrathecal morphine reduced leg lift-

induced vocalizations [635]. Spinal nerve ligation at the L5

level produced significant tactile allodynia in the ipsilateral

hindpaw that was blocked by morphine, but not U50488H

[649]. A new model of neuropathic pain produced by unilateral

partial ligation of the rat saphenous nerve produces cold and

mechanical allodynia and theram and mechanical hyperalge-

sia with the former, but not latter reversed by morphine and

gabapentin, and all but mechanical hyperalgesia blocked by

WIN55212-5 [1241]. Cancer-induced bone pain was amelio-

rated by chronic, but not acute morphine without changing

pathophysiology in the dorsal horn, including abnormally

raised wide dynamic range nociceptive response ratio

remained high [1212]. Neuropathic cancer pain produced by

Meth-A sarcoma cells increased c-Fos positive cells in the

superficial and deep layers of the dorsal horn with SP and

CGRP up-regulated after day 18, but down-regulated after day

25. Up-regulated DYN-A was present on days 18 and 25 [1076].

Continuous or intermittent stimulation of the gastrocnemius

muscle resulted in greater nociceptive behavioral scores,

elevated sensory thresholds in continuous conditions, an

effect reversed by naloxone; intermittent stimulation

increased spinal dorsal horn c-Fos labeling [1260]. Eccentric

contraction of the extensor digitorum longus muscle of the rat

produced mechanical hyperalgesia on the Randall–Selitto test,

failed to alter tactile responsivity to von Frey hairs, activated

c-Fos in the superficial dorsal horn following muscle com-

pression, and was blocked by morphine pretreatment [1145].

3.1.2. Supraspinal circuitsAn automated movement detection system was validated for

use of nociceptive behaviors (agitation) on the formalin test

using different formalin concentrations and its reversal by

morphine [1309]. Mice deficient in Brn-3a displayed increases

in small and decreases in medium-to-large SP immunoreac-

tive primary nociceptive neurons in the trigeminal ganglion,

while markedly decreasing DOR and marginally increasing

MOR in the same cells [527]. Mice overexpressing NGF or glial

cell line-derived neurotrophic factor display alterations in the

expression of genes induced by CFA administration [817].

Transposition of the greater omentum in rats increased

withdrawal latencies for both high and low levels of noxious

heat stimulation [10]. Infants born before 28 weeks of

gestational age displayed higher cumulative neonatal proce-

dural pain with lower cortisol responses to stress and lower

facial reactivity to pain relative to infants born between 29 and

32 weeks [447]. A novel thermal operant behavioral assay in

which animals are trained to place their face against a

stimulus thermode for food reinforcement was used in

inflammation and analgesic studies and measured both

reward outcomes and the number and duration of facial

contacts [854]. Osteoarthritis induced by injection of iodoa-

cetate, but not papain into the knee produced decreased bone

mineral content and density, necrosis of articular cartiledge,

osteophyte formation and pain as measured by alterations in

weight bearing with the latter effect reversed by morphine

[944]. A new method of measuring primary hyperalgesia by

measuring compression withdrawal thresholds of the gastro-

cnemius muscle or the knee joint with a device of strain

gauges attached to forceps is useful in evaluating carrageenan

or carrageenan-kaolin-induced pain [1097]. Ligation of the

common peroneal nerve near the head of the fibula produces a

morphine-resistant behavioral allodynia and thermal hyper-

algesia together with intact motor function [1214]. Post-

incisional allodynia can be induced in the hairy skin of the

rat that is blocked by subcutaneous bupivacaine [308]. Induced

pancreatic cancer in mice produces morphine-reversible pain

behaviors only when the cancer is well advanced [703]. A

murine model of bone pain indicated that behavioral

manifestations of pain emerged in parallel with bone

destruction, an effect blocked dose-dependently by opioid

agonists [320]. Bone cancer pain can be modulated by anti-

nerve growth factor therapy that accompanies markers of

peripheral and central sensitization [1057]. As an animal

model for acute trigeminal pain, administration of a 5 M

sodium chloride solution into the rat eye produced eye wiping

that was dose-dependently reduced by morphine with a

strong correlation to morphine’s effectiveness on the hot-

plate test [341].

3.2. Opioid analgesia

The following sub-sections examine advances in our under-

standing of opioid-mediated analgesia in the past year

especially as they pertain to the opioid receptor subtypes

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83402

and their genes: (i) mu agonists and receptors, (ii) delta

agonists and receptors, (iii) kappa agonists and receptors, and

(iv) OFQ/N and the ORL-1 receptor. Finally, human studies

related to opioid-mediated analgesia are covered in Section

3.2.5.

3.2.1. mu Agonists and receptorsA review [954] examines the roles of opioid systems,

particularly the molecular and cellular mechanisms in the

treatment of neuropathic pain. A second review [957] proposes

that during inflammatory processes, opioid peptides can be

secreted from immunocytes, occupy peripheral opioid recep-

tors on sensory nerve endings, and produce analgesia by

inhibiting excitability of these nerves or the release of

proinflammatory neuropetides. A third review [914] covers

the molecular biology of opioid analgesia focusing on variants

of the cloned MOR.

3.2.1.1. Morphine. A review [726] summarizes the actions of

the major morphine metabolites. Adeno-associated viral

vectors containing MOR into the sciatic nerve up-refulates

MOR in DRG for up to six months that is accompanied by a 5.4-

fold increase in morphine’s analgesic potency [452]. Intrathe-

cal morphine produced short-term (3–5 h) analgesia and a

longer lasting (1–2 days) hyperalgesia on a paw pressure test

with the latter, but not former effect blocked by ketamine

[1220]. Morphine and bupivacaine, but not ibuprofen or

lidocaine blocked the increase in c-Fos expression in the

superficial laminae of the subnucleus caudalis in the rat

trigeminal nucleus following exposure of the tooth pulp [721].

Morphine analgesia as measured by the kaolin-induced,

bradykinin-mediated writhing test was maximal at 7 h into

the light cycle and minimal at 7 h into the dark cycle, an effect

consistent with the time course of significant dark cycle

decreases in the hepatic enzyme glutathione [246]. Inter-

leukin-12 produced a mechanical, but not thermal hyper-

algesia that was antagonized by morphine pretreatment

[1234]. Morphine produced naloxone-reversible inhibition of

nociceptive vascular responses induced by intra-arterial

propofol and capsaicin [28]. Morphine increased signal

intensity of fMRI BOLD contrast in the cingulate cortex,

amygdala, thalamus, hypothalamus and PAG in a naloxone-

reversible manner; the same structures were activated by

formalin and the latter response was attenuated by morphine

pretreatment [1061]. Morphine decreased acute nociceptive

behaviors on the formalin test without altering the degree of

sensitivity developed in formalin-induced hind paws for up to

48 h after injection. However, morphine blocked the formalin-

induced increases in enzyme protein levels of heme oxyge-

nase, NOS and soluable guanylate cyclase among others

[1073]. Very low doses of dextro-morphine pretreatment

blocked analgesia induced by higher doses of levo-morphine

with the former effect blocked by opioid-insensitive dextro-

naloxone, opioid-sensitive levo-naloxone and the glial inhi-

bitor, propentofylline [1298]. Development of neuropathic pain

and increased spinal expression of c-Fos and PKCgamma was

retarded by pre-injury administration of clonidine, fluoxetine

and morphine with the latter reversed by serotonergic and NE

antagonism [971]. Selective attenuation of pain affect as

indicated by a decrease in the aversiveness of noxious

cutaneous stimulation in animals with ligation of the L5

spinal nerve with no alteration of mechanical paw withdrawal

threshold was observed following low doses of morphine

applied systemically and into the NAC [652]. Morphine,

fentanyl, DPDPE and SNC 80 decrease plasma extravasation

induced by carrageenan in a receptor subtype-specific manner

with mu, but not delta agonist-induced effects blocked by H(2)

and H(3) receptor antagonists [1008]. Mechanical allodynia

following spinal nerve transaction was reduced by systemic

and spinal morphine, effects sensitive to morphine tolerance.

Whereas protein levels in glial fibrillary acidic protein were

elevated in both systemic and spinal morphine groups, it was

further elevated in the latter group [1169]. Epidural morphine

doses combined with ketamine provided intraoperative pain

relief in dogs undergoing ovariohysterectomy [7]. Pre-opera-

tive morphine and bupivacaine paired with immediate post-

laparotomy interleukin-1 decreased the pain-related weight

and intake losses observed in rats [1066]. Morphine signifi-

cantly increased avoidance latencies to intense thermal

stimuli in the terrestrial Gastropoda Megalobulimus in a

naloxone-reversible manner, whereas naloxone alone pro-

duced significant decreases in latencies to this thermal

response [5]. The morphine metabolite, M6G had an enhanced

analgesic profile following vectorization (Syn1001) that mark-

edly enhances brain uptake of M6G [1174]. M6G-induced

analgesia was enhanced and responsivity to noxious stimuli

reduced in C57BL/6-Mc1R(e/e) mutant mice and human

redheads with non-functional MC1 receptors [813]. M6G-

induced analgesia is decreased in mice lacking multidrug

resistance protein 3, an effect accompanied by an inability to

excrete M3G from the liver into the bloodstream [1352].

The ability of intravenous morphine to significantly inhibit

the evoked response of dorsal horn neurons occurred in intact

and spinally transected rats with reversal of this effect in both

groups noted following the mu antagonist, CTAP and the Ach

antagonist, atropine [203]. Morphine-induced inhibition of the

evoked response of dorsal horn neurons was decreased by

ligation of L5 and L6 input with the GABA-A antagonist,

bicuculline blocking the opiate action in intact, but not nerve-

damaged animals and the glycine antagonist, strychnine

blocking the opiate action in both groups [204]. Medisorb

naltrexone, a once-a-month long-acting injection, antago-

nized morphine analgesia across its time course, an effect that

correlated with sustained plasma naltrexone levels and

increased brain MOR density [268]. 6beta-Naltrexol was

equipotent to naloxone, but less potent than naltrexone in

blocking morphine analgesia and locomotor activity, and was

far less potent than naloxone and naltrexone in precipitating

withdrawal in acute or chronic morphine treatment [962].

3.2.1.2. mu Opioid agonists. 60-Guanidinonaltrindole selec-

tively activates only opioid receptor heterodimers, but not

homodimers, and is analgesic following spinal but not

supraspinal administration, arguing for heterodimer organi-

zation tissue-specificity [1242]. DAMGO-induced analgesic

responses elicited from the baso-lateral amygdala were

blocked by naltrexone, BFNA, and pertussis toxin, a G-protein

inhibitor [1079]. A peptide nucleic acid AS directed against

MOR, but not its mismatch control abolished DAMGO-induced

analgesia, but not analgesia induced by the DOR agonist,

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3403

SNC80, an effect that occurred in the absence of effects

upon [(35)S]GTPgammaS responsiveness or MOR autoradio-

graphy [948]. Osteosarcoma-induced hyperalgesia was

blocked by peritumoral administration of: DAMGO that was

reversed by naloxone methiodide and cyprodime, DPDPE

that was reversed by naloxone methiodide, and NTI, and

U50488H that was reversed by naloxone methiodide and NBNI

[46].

3.2.1.3. mu Opiate agonists. A review [727] summarizes the

major opiate agonists in terms of their pharmacokinetic and

pharmacodynamic modeling. The 6-amino acid conjgates

(glycine, alalnine and phenylalanine) of 14-O-methyloxymor-

phone were more potent than morphine and as potent as

fentanyl following systemic and central administration on the

tail-flick test, produced anti-hyperalgesic effects on the

formalin test, and were blocked by the peripherally acting

antagonist, naloxone methiodide [381]. Buprenorphine dis-

played additive or synergistic analgesic effects with morphine,

oxycodone, hydromorphone and fentanyl with morphine and

fentanyl showing full efficacy after the decline of an acute

buprenorphine effect. Burpenorphine analgesia is fully

blocked by naloxone, naltrexone and clocinnamox [615].

Morphine, methadone and codeine were effective in blocking

the mechanical and cold allodynia induced by photochemi-

cally induced spinal cord injury, whereas the first two, but not

the third, were effective in blocking allodynia in spared nerve

injury and chronic constriction injury [326]. In comparing a

range of opiates on a series of preclinical measures, fentanyl

had the strongest analgesic potency, whereas buprenorphine

had ceiling effects indicating an increased safety margin for

side effects, but decreased analgesic efficacy [794]. Fentanyl

analgesia on acute nociceptive tests and anti-hyperalgesia on

the carrageenan-induced monoarthritis test was potentiated

by sub-analgesic doses of the NSAID, nitroparacetamol,

presumably due to a blockade of fentanyl-induced tolerance

[386]. Fentanyl-induced reversal of the mechanical hyperal-

gesia elicited by carrageenan was blocked by the ATP-sensitive

K+ channel antagonists, glibenclamide and tolbutamide, but

not by Ca2+-activated K+ channel blockers, ChTX, apamin,

TEA, 4-AP or cesium [1003]. However, fentanyl-induced short-

term enhancements of hyperalgesia induced by inflammatory

or incisional pain were blocked by nitrous oxide [995]. Codeine

analgesia on the formalin test was blocked by naloxone, L-

NAME, glibenclamide, tolbutamide, 4-AP and TEA [887].

Fentanyl produced analgesia in a rat surgical preparation,

but produced exaggerated post-operative pain, allodynia and

hyperalgesia at the incision site; this was blocked by ketamine

pretreatment [996]. The onset and offset of fentanyl and

buprenorphine analgesia is mainly determined by biophase

distribution as assessed by pharmacokinetic–pharmacody-

namic modeling [1320]. Oxycodone’s analgesic responses were

reversed in diabetic and non-diabetic mice by mu, but not

delta antagonists, whereas kappa antagonism reduced oxy-

codone-induced analgesia only in diabetic mice [865].

The peripherally acting mu opiate agonist, DiPOA and

morphine reduce inflammation-induced hyperalgesia without

affecting edema when they are applied to the inflammation

site. Central DiPOA and central and systemic morphine reduce

both hyperalgesia and edema in this preparation [1283].

Loperamide, like morphine produced analgesia on the

formalin test which was blocked by naloxone methiodide,

and enhanced by central pretreatment with NMDA receptor

antagonists, memantine and CGP37849, but not by NMDA/

glycine B antagonism [1058]. Loperamide administered sub-

curtaneously, intraperitoneally or locally over the bone cancer

mass inhibits the cancer-induced thermal and mechanical

hyperalgesia, an effect blocked by naloxone methiodide and

cyprodime, but not NBNI or naltrindole [797]. Intrathecal

loperamide produced more potent and prolonged analgesia

than morphine that was partially antagonized by naloxone

[979]. KT-90, a synthesized compound binding MOR, DOR and

KOR, produces analgesia on the mouse acetic acid writhing

test that is blocked fully by BFNA, partially by NBNI, but not by

NTI. KT-90 ameliorated scopolamine-induced memory

impairment that was mediated by sigma, but not KOR

antagonists [499].

3.2.1.4. Endomorphins. Endomorphin-1 pretreatment in the

ventrolateral PAG blocked subsequent morphine analgesia in

the same site, an effect blocked by the opioid levo-isomer, but

not dextro-isomer of naloxone. Only lower doses of endo-

morphin-2 in the ventrolateral PAG blocked subsequent

morphine analgesia, an effect blocked by levo-naloxone, 3-

methoxynaltrexone and antisera directed against DYN, but

not against BEND, Menk, Lenk, SP, CCK or kappa or delta

antagonists [1177]. Endomorphin-1 reduced joint afferent

nerve activity in normal and acutely inflamed knee joints in

a CTOP-sensitive manner, but failed to affect this activity in

chronically inflamed joints. This failure to observe effects was

accompanied by MOR protein loss in the ipsilateral L3-L5 DRG

[691]. Whereas endomorphin-2 analogues modified in the

third position failed to produce more potent analgesia than the

parent compound, [D-Phe3]-morphiceptin; [D-1-Nal3]-morphi-

ceptin were more potent in analgesic assays than morphi-

ceptin [353]. Moreover, endomorphin-2 analogues with

substitution of Asp, but not Lys in the second position

produced a potent naloxone-sensitive and NBNI-sensitive

analgesia, but no binding affinity at mu or kappa receptors

[542]. Moreover, [Sar2]-endomorphin-2 displayed postent

analgesia on the hot-plate test following ventricular admin-

istration [637]. The endomorphin analogues, endomorphin-

1[psi] and endomorphin-2[psi] possess only partial agonist

potency, but produce strong analgesic effects [1371]. The

endomorphin-2 analogues, [D-1-Nal(4)]- and [D-2-Nal(4)]-endo-

morphin-2 each blocked endomorphin-2-induced analgesia,

and showed potent affinity relative to endomorphin-2 [636]. A

D-pro-2 analog of Tyr-W-MIF-1 attenuated DAMGO and

endomorphin-1, but not endomorphin-2 analgesia, whereas

naloxonazine blocked analgesia induced by DAMGO, endo-

morphin-1, endomorphin-2 and Tyr-W-MIF-1 [1271]. [Dmt1]-

endomorphin-2 produced analgesia on the hot-plate and tail-

flick tests in which naloxone and BFNA produced blockade on

both tests, the mu-1 antagonist, naloxonazine only was

effective on the hot-plate test, and NTI was only effective

on the tail-flick test [554].

3.2.1.5. BEND. Central and spinal BEND-induced analgesia on

the tail-flick test was attenuated by formalin pretreatment to

both hindpaws, particularly in mice treated with formalin 40 h

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83404

earlier. This treatment increases hypothalamic POMC levels

2 h, but not 40 h after induction [469].

3.2.1.6. Manipulations affecting mu analgesia. Knockdown of

the regulator of G-protein signaling, RGSZ2 augmented the

analgesic responses to morphine and DAMGO, but failed to

affect that of DPDPE or Delt II; this effect also increased

tolerance to higher doses of morphine [399]. Antisera directed

against DYN A(1–17), SP or CCK-8 enhanced the ability of

spinal morphine to produce anti-allodynic effects in mice with

partial sciatic nerve ligations [1297]. Mice with KO of GIRK1 and

GIRK2, concentrated in close apposition to mu opioid

receptors in the superficial spinal cord, display blunted

analgesic effects to mu and delta, but not kappa opioid

agonists [769]. AS directed against okadaic acid-sensitive Ser/

Thr protein phosphatases PP2A and PP5 reduced morphine

analgesia and decreased their morphine-induced expression

levels in the PAG and spinal cord [742]. CRF KO mice failed to

show circadian differences in MOR expression, and no

circadian differences in morphine analgesia. Corticosterone

treatment to CRF KO mice induced MOR expression in mouse

brainstem and enhanced morphine analgesia [1326]. A

phosphorothioate oligodeoxynucleotide AS, but not a mis-

sense to the gamma2 G-protein subunit blocked analgesia

induced by mu, kappa, cannabinoid and alpha-2-adrenore-

ceptor agonists [1223]. Whereas baclofen enhanced morphine

and fentanyl analgesia in a GABA-B antagonist-sensitive

manner, it suppressed retching and vomiting induced by

morphine and blocked CPP induced by morphine and fentanyl

[1139]. G-protein-coupled receptor 10 KO mice displayed

potentiations in morphine and naloxone-sensitive stress-

induced analgesia and morphine CPP, reductions in morphine

tolerance and blocked the anti-opioid effects of neuropeptide

FF. Prolactin-releasing peptide promoted hyperalgesia and

reduced morphine analgesia in wild-type, but not KO mice

[662]. A highly selective NPFF2 agonist, dNPA, reduced

morphine analgesia following ventricular and systemic

administration [1013]. Ibuprofen, but not aspirin or ketorolac,

potentiated the analgesic actions of hydrocodone and oxyco-

done, but not fentanyl or morphine [1353]. Intrathecal, but not

systemic morphine analgesia is reduced in mice lacking the

adenosine A1 receptor, and these mice display exaggerated

hypersensitivity to heat, but not mechanical stimui following

carrageenan, and increased neuropathic pain responses to

heat and cold following partial sciatic nerve injury [1302].

Interleukin-1-beta blocked morphine analgesia, whereas

chronic blockade or inactivation of interleukin 1 receptors

potentiated morphine analgesia and prevented the develop-

ment of morphine tolerance [1067]. Intrathecal pretreatment

with the adenosine A1 antagonist DPCPX reversed morphine’s

ability to block the naloxone-sesnitive mechanical hypersen-

sitivity following spinal nerve ligation [1363]. RVM CCK

produced tactile and thermal hypersensitivity as well as a

rightward shift in intrathecal morphine analgesia that was

blocked by CCK-2 receptor antagonism or dorsolateral

funiculus lesions. Morphine tolerance producing tactile and

thermal hypersensitivity was blocked by RVM CCK-2 receptor

antagonism [1308].

Dextromethorphan, a NMDA antagonist, enhanced mor-

phine analgesia on the tail-flick test and increased serum

morphine, yet decreased codeine analgesia while decreasing

the serum concentration of its active metabolite [201].

Synergistic analgesic interactions without motor impairment

were noted on the second phase of the formalin test for

morphine and the NMDA antagonist, amantadine [1105].

Morphine analgesia elicited from the PAG was reduced by

both MK-801 and L-NAME [548]. Whereas morphine analgesia

on the hot-plate test was enhanced by the competitive NMDA

antagonist, LY235959, the glycine site NMDA antagonist, R(+)-

HA-966 and polyamine/NR2B NMDA antagonist, ifenprodil, l-

methdone-induced analgesia was only enhanced by LY235959

[360]. The MC-4 antagonist, HS014 shifted the morphine’s

analgesic dose–response curve two-fold to the left without

affecting morphine potency in locomotor activity; a similar

pattern was observed in A(y) mice, a genetic model for MC-4

receptor blockade [325]. Whereas a selective NPFF-1 receptor

agonist produced anti-opioid effects on the tail-flick test, a

selective NPFF-2 receptor agonist augmented morphine

analgesia [958]. The NSAID, HCT-2037 was very effective in

enhancing in a naloxone-insensitive manner the fentanyl-

induced anti-hyperalgesia in carrageenan-induced monoar-

thritic rats tested for noxious mechanical stimulation [387].

The L-type calcium channel blocker, nimodipine displayed

enhanced analgesic effects with morphine after intrathecal,

but not systemic administration [1232]. The calcium channel

blocker, nifedipine potentiated morphine analgesia on the

tail-flick test that was enhanced further in adrenalectomized

rats, and reversed by corticosterone replacement therapy

[330]. The tricyclic antidepressant, doxepin increased noci-

ceptive thresholds on the paw pressure test, reduced

formalin-induced pain behavior, and potentiated morphine

analgesia on the formalin test [1294].

Green tea extract reinstated the full expression of mor-

phine analgesia in diabetic rats, an effect that was potentiated

further by L-NAME, but blocked by L-arginine [1089]. The

bacterial endotoxin, lipopolysaccharide inhibits morphine

analgesia, but is reversed by pretreatment with either the

non-competitive NMDA antagonist, MK-801, the glial meta-

bolic inhibitor, fluorocitrate or naloxone [555]. Fangchinoline,

a non-specific calcium antagonist decreased morphine

analgesia, but not morphine tolerance on the tail-flick, but

not tail-pinch test, actions reversed by a serotonin, but not NE

precursor [337].

3.2.2. delta Agonists and receptorsDirect interaction between the SP domain of protachykinin

and DOR is responsible for sorting DOR into large dense core

vesicles, and thereby mediating spinal DOR-sensitive analge-

sia [453]. Whereas morphine displays analgesia on writhing,

formalin and thermal hyperalgesic assays as well as produ-

cing adverse effects on gastrointestinal, respiratory depres-

sive and motor measures, the delta agonist, SNC80 was most

effective on the writhing test, and of limited efficacy on

thermal hyperalgesia without adverse effects [391]. SNC-80

decreased hyperalgesia induced by prostaglandin E2 that was

reversed by both delta-1 and delta-2 antagonists as well as by

blockade of the NO/cGMP pathway [899]. RB101, an Enk

catabolic enzyme inhibitor, produced analgesia in wild-type,

but not MOR KO mice. However, wild-type and MOR KO mice

displayed similar changes in locomotor activity, anxiety

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3405

measures and motivation measures following RB101 [858].

Pre-pro-Enk mRNA expression was increased in the ipsilateral

trigeminal subnuclei caudalis and oralis 24 h following

noxious tooth movement [53]. Menk suppressed responses

to nociceptive stimuli, and Menk administration during

acquisition of sensitization led to the complete suppression

of the facilitation of responses to tactile stimulation of the

head in the common snail [860]. Melatonin significantly

enhanced analgesic responses induced by Delt, but not by

endomorphin-1, an effect blocked by the melatonin antago-

nist, luzindole [686].

3.2.3. kappa Agonists and receptorsU50488H-induced analgesia was unaffected by the serine/

threonine protein phosphatase inhibitors, okadic acid and

cantharidan, antagonists that dose-dependently blocked

analgesia induced by clonidine and baclofen [818]. Diabetic

mice displayed significantly less analgesia following spinal

administration of the KOR-1 agonist, CI-977, following

supraspinal administration of the KOR-1 agonists, ICI199941

and R-84760, and following supraspinal and spinal adminis-

tration of the KOR2/3 agonist, TRK-820 [872]. Big DYN, a

combination of DYN A and B produces biting behaviors

following intrathecal administration in a manner similar to

that observed following N-ethylmaleimide in uninjured

animals, and its inhibition of degradation is responsible for

the latter’s effect [1162]. Intrathecal DYN A and DYN B

produced analgesia in capsaicin-treated animals, effects

enhanced by cysteine protease inhibitors [1161]. Acupuncture

analgesia released less immunoreactive DYN than immunor-

eactive Menk [1202]. A bridged morphinan, BU74 produced

long-lasting KOR agonist activity in biochemical and analgesic

assays, and subsequently had antagonist actions against

kappa and mu agonists on the tail-flick test, and against delta,

kappa and mu agonists on the writhing test [521]. Pruritic

responses induced by cholestasis bile duct removal signifi-

cantly decreased KOR and DOR opioid binding in the dorsal

hypothalamus that was accompanied by a decrease in serum

DYN A levels [532]. A kappa agonist, TRK-820 and naltrexone

inhibited spontaneous scratching behavior noted in MRL/lpr

mice [1211]. Moreover, the kappa agonist, nalfurafine,

decreased itching behavior and sleep disturbances in patients

with uremic pruritus [1287]. A series of 3-substituted analo-

gues of a parent kappa agonist, designed to limit access to the

CNS were more effective than ICI204448 in producing

analgesia on the rat formalin and mouse acetic acid writhing

assays, but not on the mouse platform sedation test [641].

Pyrollic N-benzylation of NBNI produced very short MOR

agonist activity, but very prolonged KOR antagonist activity in

mouse antinociceptive assays [188].

3.2.4. OFQ/N and ORL-1 receptorOFQ/N continues to present a complex picture concerning its

role in pain responses producing both ‘‘pro-nociceptive’’ and

‘‘anti-nociceptive’’ actions depending on such factors as site of

administration, dose and time course. Indeed, a review [486]

indicates that OFQ/N induces pro-nociceptive effects in the

RVM by inhibiting opioid-activated pain-inhibiting neurons,

and anti-nociceptive effects by inhibiting pain-facilitating

neurons. Whether OFQ/N produces pro- or anti-nociceptive

effects depends on whether the pain-facilitastory or pain-

inhibitory neurons are active in the RVM.

3.2.4.1. Pro-nociceptive actions. NOR mRNA in the PAG, DRN

and NRM is signitifantly up-regulated 1 week following sciatic

nerve chronic constriction injury, and persists for up to 2

weeks [736]. The ability of OFQ/N to produce nociceptive

behaviors and antagonize analgesia elicited by DAMGO,

DPDPE, Delt and U50488H was in turn reversed by supraspinal

administration of nocistatin [1053]. UFP-102, a potent and

selective agonist of OFQ/N decreased tail-flick latencies with

higher potency and longer durations than OFQ/N, increased

locomotor activity, and decreased HR, MAP and urinary

sodium excretion [161]. Both OFQ/N and one of its agonist

analogues blocked paracetamol-induced analgesia on the hot-

plate test, effects reversed by the NOR antagonist, UFP-101

[1036]. Peripheral and central treatment with the NOR agonist,

JTC-801 reversed tactile allodynia induced by L5/L6 spinal

nerve ligation, suppressed the second, but not first phase of

formalin pain, and reduced Fos-like immunoreactivity in the

dorsal horn of the spinal cord [1154]. Orexin A, and to a lesser

degree orexin B elicited analgesia on thermal, mechanical and

chemical nociceptive assays following systemic, ventricular

and intrathecal treatment, and blocked OFQ/N-induced

nociceptive responses [810].

3.2.4.2. Antinociceptive actions. Intraplantar OFQ/N and two of

its fragments (OFQ(1–11) and OFQ(1–13)) produced antinoci-

ception and decreased the rate of capsaicin desensitization

[1026]. The maintenance, but not the development of

secondary mechanical allodynia induced by capsaicin treat-

ment was attenuated by intrathecal treatment with OFQ/N,

but not the NMDA antagonist, MK-801 [866]. A similar, though

weaker anti-allodynic effect was noted for the NOR agonist,

Ro64–6198 in neuropathic rats tested for mechanical and

thermal stimuli in a NOR antagonist-sensitive manner [867].

Patients displaying migraine attacks displayed lower plasma

OFQ/N levels with reductions most acute in the first 3 h of a

migraine attack, suggesting dysregulation of the trigemino-

vascular OFQ/N system [328].

3.2.5. Human studiesA review [728] indicated that a common MOR polymorphism is

associated with higher demands for opiates in pain relief and

decreased morphine-induced pupil constriction and analge-

sia.

3.2.5.1. Volunteers. Volunteers exposed to skin burn or

electrical pain disply dose-dependent increases in mechanical

pain thresholds and decreased secondary hyperalgesic areas

following alfentanil and morphine [1050]. Application of

electrically induced pain stimuli to human volunteers over

150 min resulted in significant decreases during the sessions

in pain ratings, area of punctuate hyperalgesia and area of

allodynia with both effects reversed by ultra-low doses of

naloxone [621]. Oxymorphone immediate-release tablets

produced plasma dose-proportionality and correspondingly

increased plasma 6-OH-oxymorphone and oxymorphone-3-

glucuronide in healthy human volunteers [9]. Co-ingestion of

oxycodone, but not diphenhydramine resulted in delayed

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83406

absorption of high doses of acetaminophen in healthy human

volunteers [466].

3.2.5.2. Dental pain. Etoricoxib was as effective as oxycodone–

acetaminophen and codeine–acetaminophen combinations in

relieving dental impaction pain [751]. A combination of

oxycodone and ibuprofen was superior to oxycodone–acet-

aminophen and hydrocodone–acetaminaphen in relieving

post-operative pain to remove impacted third molars [707].

Local anesthesia with articaine paired with peripheral

morphine was effective in treating pain following surgery of

inflamed oral and maxillofacial tissues [562].

3.2.5.3. Chronic pain. There was no association between the

doses of opioids and sedatives on the last day of life and

survival in an Austalian inpatient palliative care population in

a hospice [423]. Deep brain stimulation of the periventricular

gray and thalamus in patients with phantom limb pain

reduced pain intensity by 62% over a 13-month period and

reduced morphine consumption [104]. Placebo-induced pain

relief in patients with sustained pain was accompanied by

activation of MOR-mediated neurotransmission in the ante-

rior cingulate, dorsolateral prefrontal cortex, insular cortex

and NAC [1385]. However, patients with chronic discogenic

back pain could be subdivided with the group responding

poorly to morphine or placebo analgesia displaying higher

levels of psychopathology and negative affect [1270]. Higher

BEND levels were found in the synovial lavage fluid of the

temporomandibular joint of patients with closed lock; this was

not correlated with clinical pain parameters [565]. Pain

duration and analgesic treatment could not be adequately

predicted in a patient sample with chronic whiplash-asso-

ciated pain [678]. Methadone through its NMDA antagonist

activity appears effective in treating intractable neuropathic

pain [828]. A combination of morphine and the NMDA

antagonist, dextromethorphan failed to produce enhanced

analgesia or reduced tolerance in chronic non-neuropathic

pain patients participating in a multi-center study [388]. Both

controlled-release and extended-release forms of oxymor-

phone were equally effective in the treatment of chronic back

pain [467], and controlled-release oxycodone was effective in

treating persistent pain associated with osteoarthritis [768] to

a greater degree than placebo [1350]. Similarly, extended-

release and immediate-release hydromorphone produced

comparable relief in patients with persistent moderate to

severe pain [446]. A number of opioids were effective in

reducing pain severity in patients with different spinal

pathologies with common side effects of constipation and

sedation [747]. Although transdermal fentanyl and sustained

release morphine equally relieved chronic low back pain, the

former has less associated constipation [17]. Individual

administration of gabapentin and morphine were more

effective in pain relief in neuropathic pain patients than their

combined actions [408]. Treatment of traumatic pain in the

emergency room revealed no differences in PCA as compared

to titrated intravenous opioid treatment in pain relief, patient

satisfaction or incidence of adverse side effects [331].

Morphine and fentanyl were comparable in relieving severe,

acute pain in a pre-hospital setting [390] as were the pairing of

either oxycodone or hydrocodone with acetaminophen [760].

Intranasal fentanyl was as effective as oral morphine in

pediatric burn patients for dressing changes [118]. Periodic

(60 h) cessation of controlled-release morphine to chronic pain

patients failed to show dependence or craving, but did produce

detrimental effects of increased pain intensity on activity,

mood, relationships, sleep and enjoyment of life [238].

Oxymorphone extended release treatment provided strong

long-lasting (12 h) pain relief for moderate severe osteoar-

thritis up to 12 months after treatment [789], and buccal

oxycodone was effective in relieving short-term abdominal

pain in children [617]. Adding ultralow doses of naltrexone to

oxycodone both enhanced and prolonged analgesia in chronic

pain patients with osteoarthritis [210]. Methadone was

effective in the treatment of chronic neuropathic pain [20].

Transdermal buprenorphine was effective in the treatment of

neuropathic pain [694]. Encapsulated chromaffin cell-loaded

devices rich in Menk and catecholamines were safe, retrie-

vable and maintained themselves in serum-maintained media

over 8 days as a test for use in chronic pain management

[1291]. Epidural diamorphine was more effective than epidural

levobupivacaine in producing rapid and long-lasting (�1 day)

analgesia in chronic stump pain in amputees [322]. A review

[362] indicated that morphine was prescribed most often for

treatment of pain in the elderly. Chronic pain patients taking

morphine or hydromorphone show comparable driving ability

as normals [144]. Atopic dermatitis, which produces chronic

itching, significantly down-regulates MOR expression in the

epidermis by producing internalization of the mRNA wherein

it is concentrated in the subcorneal layers rather than the

suprabasal layers [100].

3.2.5.4. Cancer pain. A review [267] indicates the utility of a

patch form and sublingual buprenorphine to produce analge-

sia with lessened constipation in cancer patients. In a choice

of morphine intervals for the treatment of cancer pain, most

patients chose a once-a-day regimen [464]. Cancer patients

who carried the common allele at 1182 G/A, 5864 G/A, 8622 T/C

and 11143 G/A in the beta-arrestin-2 gene switched from

morphine to alternative opioids during treatment [1010]. The

Val158Met polymorphism of the human catechol-O-methyl-

transferase gene in cancer patients may be important because

patients with the Val/Val phenotype require more morphine

than the Val/Met and Met/Met genotypes [967]. Morphine

bioavailability is increased in patients with primary liver and

secondary metastatic carcinoma, indicating careful treatment

[626]. Morphine reduced cancer pain with its metabolites

responsible for the immunologic actions of T-cell proliferation

and increased immunoglobulin G [476]. Both subcutaneous

and intravenous morphine were effective in titrating persis-

tent exacerbation of cancer pain [323]. Oral morphine

produced more effective analgesia when paired with trans-

dermal buprenorphine than transdermal fentanyl in a retro-

spective analysis of patients with cancer and noncancer pain

[1095]. Opioid rotation from morphine to fentanyl appeared

effective in delirious cancer patients [823]. Oxymorphone

extended release treatment could be effectively substituted

for pain relief in cancer patients stabilized on morphine-

controlled release or oxycodone controlled release treatment

[1100]. Using a standard-injection pen administering hydro-

morphone, morphine or sufentanil, breakthrough pain was

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3407

managed in cancer pain to a degree equivalent to 25 mg of

subcutaneous morphine [324]. Oral administration of acet-

aminophen, indomethacin and morphine, but not COX-1 or -2

inhibitors produced analgesia for bone cancer pain with

subanalgesic doses of morphine enhancing acetaminophen

analgesia [1023]. A bupivacaine continuous wound infusion

system was tolerated in gynecologic oncology patients [645].

Both intravenous and subcutaneous morphine treatment was

effective for cancer pain in resource-scarce developing nations

[624]. Use of morphine PCA in pediatric oncology patients

necessitated the use of naloxone to reverse respiratory or

neurological effects [31]. Elderly patients receiving chemor-

adiotherapy for advanced pancreatic carcinoma displayed

greater sensitivity to morphine-induced relief of abdominal

and back pain than younger patients [824]. Cancer patients in

the United Kingdom typically started transdermal fentanyl

treatment later after diagnosis than those treated with

sustained release morphine; costs of palliative care were

similar between groups [455]. Increased awareness towards

pain treatment appears to explain the increased use of opioids

in Danish cancer patients [545]. The most common switching

in opioid care in German cancer patients was from oral to

parenteral morphine with lesser occurrences of changing

opioid agonist treatment [832]. A revised Edmonton Staging

System method of assessing pain control in advanced cancer

patients was more effective than the original assessment

instrument [334].

3.2.5.5. Surgical pain. Increased depth of anesthesia as mea-

sured by auditory evoked potentials resulted in higher

morphine PCA requirements in the ensuing 24 h [489].

Increased consumption of opiates for post-operative pain

relief was noted in 2002 relative to 2000, particularly in a post-

anesthesia care unit at the Mayo Clinic; the increase was not

associated with increased hospital stay or post-operative

nausea and vomiting, but rather by compliance with the Joint

Commission for Accreditation of Health Care Organizations

Pain Initiative [367]. Continuous intravenous morphine

analgesia delivered with elastomeric infusors was effective

in post-operative pain relief in burn patients [395]. Although

intravenous administration of morphine and its metabolite

produced similar degrees of post-operative analgesia follow-

ing major surgery, the latter had a slower initial onset [472].

Low doses of intrathecal morphine facilitated early extubation

after cardiac surgery and lowered post-operative opioid

requirements [912], were effective in radical retropubic

prostatectomy [1140] as well as in minimally invasive direct

coronary bypass grafting [1382]. Nebulized morphine was as

effective as PCA morphine in producing analgesia in post-

operative acute thoracic pain with fewer cardiac and sedative

side effects [379]. Epidural single-dose extended-release form

of morphine (Depodur) was as effective as repeated epidural

morphine for pain relief after lower abdominal surgery except

for instances of breakthrough pain [392]. Heroin (diamorphine)

has been prescribed most frequently for post-operative pain,

myocardial infarction, pulmonary oedema and palliative care

[430]. The addition of acetaminophen to PCA morphine

reduced morphine use by 20% for 24 h after major surgery

[982]. A combination of oxycodone and ibuprofen was more

effective than either agent alone in ameliorating post-

operative pain following pelvic or abdominal surgery in

women [1093]. Naloxone treatment in post-operative pain

management was used most often in older subjects to reverse

excessive opioid-induced sedation [428]. A review [1001]

indicates that high dose buprenorphine with its long analgesic

action and high affinity should be used if analgesic require-

ments warrant, to reduce post-operative needs for other

opiates. Continuous infusion of the cholinesterase inhibitor,

physostigmine combined with morphine PCA, reduced opiate

consumption and enhanced analgesia [77]. A qualitative

systematic review [1011] failed to find systematic analgesic

effects of morphine following intra-articular administration

after knee arthroscopy. Another review [620] indicates that

fentanyl patient-controlled trans-dermal systems are as safe

and effective as morphine PCA in managing post-operative

pain.

Fifty percent of post-surgical patients using PCA morphine

persist in using words signifying sensory and affective

dimensions of pain, indicating a need for individualized

instruction [660]. Elderly patients appear to have lower post-

surgical McGill pain questionnaire scores than the younger

group and self-administer less morphine, although the

numerical rating scale for pain appeared to have the most

face validity [385]. Low doses of naloxone paired with

morphine reduced such opioid-induced side effects as pruritis

and nausea without affecting the efficacy of post-surgical PCA

in children and adolescents [783]. Combinations of intra-

articular injections of morphine, bupivacaine and epinephrine

provided post-operative pain control in patients receiving

knee arthroscopy [426]; these effects can be obtained either

pre-operatively or post-operatively [427]. Continuous femoral

blockade with bupivacaine was as effective as epidural

ropivacaine and fentanyl during total knee replacement

surgery [64]. Morphine was more effective in extending

analgesia after knee surgery following intra-articular relative

to intravenous or intrathecal administration [21], although

intrathecal morphine showed dose-dependent beneficial

results [126]. Oxycodone administered by controlled-release

or schedules did not differ in pain relief for total joint

arthroplasty [587]. Methadone is quite ineffective following

intra-articular administration in anterior cruciate ligament

reconstruction [1127], and intra-articular administration of

tramadol is as effective as morphine [12]. Combined femoral

and sciatic nerve blocks during total knee replacement

reduced post-operative morphine analgesic requirements

[932], and continuous rather than single infusion of local

anesthetic around the lumbar plexus reduces morphine

requirements after knee arthroplasty [1272]. The addition of

intra-articular methylprednisolone to morphine produced

additive analgesic effects after knee surgery [603]. Intrarticular

neostigmine and clonidine were more effective than tenox-

icam, morphine or bupivacaine after arthroscopic knee

surgery [14], whereas intra-articular bupivacaine was largely

ineffective following total knee arthroplasty [850]. A meta-

analysis revealed that morphine consumption was reduced

after 24 h in surgical patients treated with ketamine with no

difference in morphine-related adverse effects [316]. Intrao-

perative ketamine administration during total knee arthro-

plasty required significantly less post-operative morphine,

and produced quicker post-operative knee flexion [8], and was

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83408

also effective for major digestive surgery [663]. Ketamine and

nefopam treatment reduced the need for supplemental post-

operative morphine requirements following major surgery

[570]. The timing of ketamine treatment before and during

surgery is critical in affecting post-operative morphine

consumption [103]. Gabapentin was effective in reducing

post-operative morphine consumption and decreasing anxi-

ety following knee surgery [799] as well as lumbar laminect-

omy and disectomy [961]. Intrathecal clonidine produced

short-lasting analgesia and long-term anti-hyperalgesia in

patients undergoing colonic surgery reducing PCA morphine

requirements [279]. Femoral sciatic nerve block with bupiva-

caine and clonidine is quite effective in pediatric patients

undergoing anterior cruciate ligament reconstruction [1196].

Intravenous, but not perineural clonidine prolonged post-

operative analgesia after hip fracture surgery [754], and its

addition to local anesthetic improved post-operative mor-

phine analgesia for hip arthroplasty [293]. Morphine PCA and

continuous femoral nerve sheath block are also effective in

patients undergoing hip arthroplasty [1091] along with the use

of extended-release epidural morphine [1238]. In contrast,

tramadol was not as effective in patients receiving hip

arthroplasty [755], but epidural delivery may be preferable

to morphine for post-operative analgesic requirements in

children [281]. Indeed, tramadol and morphine were infra-

additive in isobolographic analyses of the treatment of post-

operative pain [762], and equally effective for pain relief

following thoractomy [1205]. Oral tramadol and acetamino-

phen combinations were effective in post-operative orthope-

dic pain [123], and a meta-analysis revealed that NSAID and

morphine combinations in PCA were more effective in treating

post-surgical pain than morphine alone [315]. Morphine

produced greater pain relief than the NSAID, ketorolac,

although their combination reduced morphine consumption

and produced fewer side effects for post-operative pain [178].

Although ketorolac and morphine produced an opioid-sparing

effect, it had limited benefit in shortening the duration of

bowel immobility in patients undergoing colorectal surgery

[199]. However, the NSAID, diclofenac, in combination with

morphine and paracetamol was effective in producing

analgesia after mastectomy and breast reconstruction [674]

and following posterior lumbar interbody fusion [1333].

Fast-track anesthesia with remifentanil and spinal mor-

phine reduced post-operative morphine consumption in

coronary artery bypass grafting patients [679] and in off-

pump coronary artery bypass surgery [1206]. A pre-operative

fentanyl challenge in conjunction with pharmacokinetic

evaluation can individualize the post-operative administra-

tion of analgesics to chronically opioid-consuming patients

[266]. Low doses of isoflurane combined with higher fentanyl

doses were more effective than the reverse combination in

early recoverey from anesthesia and post-operative pain [833].

Remifentanil paired with spinal anesthetic blockade was more

effective than remifentanil alone for cardiac surgery in infants

and children [468], but when paired with fentanyl, increased

post-operative opioid requirements in the first hour after

cardiac surgery [974]. Remifentanil was as effective as 70%

nitrous oxide in reducing post-operative opioid consumption

in patients undergoing colorectal surgery [669], and as

effective as morphine following major abdominal surgery

[638]. Remifentanil administered during sedation reduced the

duration of mechanical ventilation and complemented mor-

phine analgesia in critically ill patients requiring prolonged

mechanical ventilation [131]. Target-controlled infusion of

sufentanil achieves better analgesia than on-demand boluses

of morphine following cardiac surgery [71]. Rofecoxib admi-

nistered to thoracotomy patients displayed less post-operative

morphine consumption and improved pain relief at rest and

during coughing [176]. The COX-2 inhibitor, celecoxib admi-

nistered during spinal fusion surgery reduced post-operative

morphine requirements for up to 20 h after surgery [985]. A

caudal block supplementing sevoflurane was more effective in

regulating pain and reducing post-operative emergence

agitation than intravenous fentanyl in children undergoing

inguinal hernia repair [35].

Combined morphine and bupivacaine provided better

quality post-operative analgesia than bupivacaine alone

[1059]. Infants receiving prior surgery in the same dermatome

needed more post-operative fentanyl, had higher post-

operative pain scores and higher plasma norepinephrine

concentrations; prior surgery in another dermatome had less

drastic effects [930]. Under regional anesthesia with bupiva-

caine, a minimal dose of epidural morphine administered

immediately after hip surgery in children was established to

produce pain relief up to 12 h [173] as well as in adults

following hip fracture surgery [365]. Bupivacaine administered

into the margin or cavity of the submammary incision reduced

post-operative morphine consumption after reduction mam-

moplasty [504]. Both continuous intravenous morphine and

ropivacaine produced effective post-operative analgesia after

scoliosis correction surgery [111] with their combination

producing highly effective analgesia after lower abdominal

surgery [859] as well as for knee surgery using intra-articular

administration [1237]. Post-operative extradural morphine

and ropivacaine was more effective than PCA morphine or

systemic ropicaine and morphine treatment [45], however

given its increased cost, is less cost-effective [67]. Combined

epidural ropivacaine and fentanyl was more effective than

ropivacaine alone for coronary artery bypass grafting [63], and

epidural ropivacaine enhanced analgesia and improved early

rehabilitation for 1 week after total knee replacement [340].

However, morphine was more effective than fentanyl as an

adjunct to ropivacaine for high thoracic epidural analgesia

[1017]. Ropivacaine administered through an iliac crest

catheter reduced post-operative morphine consumption and

reduced short-term and long-term pain during motion in

patients receiving bone grafting [110]. Interscalene ropiva-

caine was more effective than subacromial ropivacaine in

maintaing analgesia following rotator cuff repair [280].

Thoracic epidural opioids were not more effective than PCA

for patients undergoing major intesintal resections [1388].

Magnesium sulfate appears to be a good adjuvant therapy with

codeine during and after coronary artery bypass grafting [116].

3.2.5.6. Caesarean pain. A single dose of epidural morphine

during labor reduced post-partum oral pain medication use

[424], and was effective in post-partum tubal ligation

procedures [763]. Neuraxial morphine in early labor did not

increase the rate of caesarean delivery, but provided greater

analgesia and shorter labor than systemic morphine [1293].

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3409

However, morphine infusions failed to provide adequate pain

relief for acute procedural pain in preterm neonates [158]. The

addition of small naloxone doses to epidural morphine

reduced pruritus, but not pain relief in women undergoing

caesarean section [550]. The addition of intrathecal morphine

to hyperbaric bupivacaine and fentanyl improves post-

operative pain relief following tubal ligation [462]. The

addition of a tramadol infusion to morphine PCA was

associated with lower pain scores and a reduction in morphine

PCA requirements in patients undergoing abdominal hyster-

ectomy [611]. However, the addition of intrathecal diamor-

phine failed to enhance intrathecal bupivacaine analgesia

during caesarean section [11], but it was more effective than

fentanyl or combined fentanyl and diamorphine for enhan-

cing spinal anesthesia during caesarean section [657].

Intrathecal isobaric bupivacaine and hyperbaric bupivacaine

produce similar analgesic effects during caesarean delivery

[168] as do single-dose sustained-release epidural morphine

[169]. Dicofenac reduced the amount of morphine used in

post-operative caesarean patients, but the level of pain failed

to differ significantly between groups [122]. Epidural analgesia

was superior to PCA in an acute pain service of caesarean and

hysterectomy patients in Saudi Arabia [34]. Reductions in

morphine consumption and pain relief in women undergoing

abdominal gynecologic surgery were positively predicted by

pre-operative self-distraction coping, emotional support and

religious-based coping [226]. Intravenous butorphanol, meper-

idine and their combination relived pain and distress during

labor with the same incidence of adverse effects [852]. A

gabapentin–rofecoxib combination was superior to individual

drug treatment for post-operative pain control in patients

receiving abdominal hysterectomy [409]; pre-operative intra-

venous morphine and post-operative osteopathic manipula-

tive treatment also produced superior analgesic results in this

patient population [414]. Parecoxib sodium and morphine

produced similar analgesic effects in women undergoing

gynecologic laparotomy surgery [749]. Oral clonidine produced

anxiolytic and analgesic effects for up to 72 h after abdominal

hysterectomy surgery, but no change in morphine PCA [495].

Oral clonidine also failed to enhance epidural morphine

analgesia in hysterectomy patients [883].

3.3. Sex, age and genetic differences

The following organismic variables play vital roles in the

mediation of opioid analgesic responses, and continue to

attract a great deal of attention: (i) sex and gender, (ii) age-

related effects, and (iii) genetic effects.

3.3.1. SexA review [1286] summarizes the status of sex differences in

pain perception and analgesia in human and animal models.

Women possessing a rare A118G single nucleotide poly-

morphism of the MOR gene displayed higher pain ratings,

whereas men with the same allele displayed lower pain

ratings, but subjects with the allele had higher overall pressure

pain thresholds [356]. Male volunteers failed to show

significant differences in morphine analgesia on heat pain,

pressure pain and ischemic pain measures relative to female

volunteers, but did show attenuated cardiovascular activity to

the ischemic pain test. Women reported more drug-averse

effects than men [357]. Male rats displayed greater analgesia

following morphine administered into the ventrolateral PAG

than female rats neonatally treated with vehicle or testoster-

one. Neonatally androgenized females had greater analgesia

than vehicle-treated females, an effect not appreciably altered

by adult gonadecomy or estrdiol replacement [174]. Morphine

analgesia was significantly greater in male relative to female

rats with no changes in opioid receptor number, binding

affinity or opioid-stimulation of G-protein in whole brain,

cortex, thalamus or spinal cord. A low dose of the long-acting

opioid antagonist, methocinnamox decreased analgesia

induced in males to that of untreated females [924]. Castration

and testosterone replacement respectively decreased and

increased mu agonist-induced analgesia in male rats, whereas

ovariectomy and hormone replacement had more variable

effects in female rats with estradiol decreasing mu agonist-

induced analgesia [1130]. Whereas morphine, buprenorphine,

butorphanol and spiradoline produced greater analgesic

effects in male rats relative to females, their reductions in

levels of temporal summation of pain were equal in both sexes

[722]. Ovariectomy decreased basal nociceptive thresholds,

but increased morphine and especially buprenorphine analge-

sia in female F344, Lewis, Long Evans and Wistar rats. During

normal cycling, morphine and buprenorphine were most

sensitive in metestrus and proestrus and least potent in estrus

[1179]. Dextromethorphan enhanced morphine analgesia in

male and ovariectomized female rats, failed to affect it in

ovariectomized females treated with estradiol, and decreased

morphine analgesia in intact female rats [443]. Morphine,

oxycodone and butorphanol were more potent in producing

analgesia and anti-hyperalgesia in male than in female rats

made arthritic with CFA [233]. Morphine dose-dependently

inhibited bradykinin-evoked unit activity in TMJ neurons in

males and diestrus, but not proestrus females; spontaneous

TMJ activity was reduced in all groups [875]. NMDA antago-

nists differentially modulated sex-dependent morphine

analgesia with MK-801 attenuating morphine analgesia on

two assays in both sexes, dextromethorphan increasing

morphine analgesia on the hot-plate test with greater potency

observed in males, and LY235959 differentially changing

morphine analgesia as functions of dose, assay and sex of

the animal [242]. The hyperalgesic effects of low doses of

morphine were more pronounced in female relative to male

rats with tolerance to this effect noted in both sexes. After

tolerance, the efficacy of morphine analgesia was enhanced in

females, and the sex differences in morphine analgesia were

attenuated [507]. Pregnant female rats displayed reduced TMJ

nociceptive responses to formalin relative to female rats

tested during estrus; pretreatment, but not co-treatment of

the kappa antagonist, NBNI enhanced the formalin-evoked

nociceptive responses in pregnant rats [40]. However, con-

tinuous infusion of steady state doses of 17-beta-estradiol or

preogesterone to ovariectomized rats failed to affect baseline

tail-flick latencies or morphine analgesia [753].

Chronic pain reduced macrophage migration inhibitory

factor in a sex-dependent manner, correlating positively with

testosterone levels and negatively with estradiol levels [19].

Women with a parental history of hypertension showed

increased pain ratings, and men with a parental history of

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83410

hypertension showed increased pain thresholds relative to

those without this history [366]. Women experienced more

severe post-operative pain and required 11% more morphine

than men during the immediate post-operative period, an

effect that disappeared in elderly patients [42]. Sex differences

in human volunteers failed to be observed for the analgesic

effects of placebo or alfentanil [880].

3.3.2. AgingNeonatal mice undergoing laparotomy displayed increased

distress vocalizations, and as adults, displayed decreased pain

behavior as adults on the tail withdrawal and acetic acid

writhing tests, effects blocked by post-operative morphine

treatment [1125]. Aging is an important variable in the

escalation of opioid doses during chronic pain with older

patients showing lower dose requirements potentially due to a

reduced rate of tolerance [141].

3.3.3. Genetic differencesA review [604] summarizes the level of opioid clinical efficacy

to be partly related to inborn properties caused by genetic

variability. Robust genetic differences among mouse strains

were for tail-clip latency in open-air and isoflurane treated

animals, a naloxone-reversible effect that correlated with

minimum alveolar concentration [814].

3.4. Opioid mediation of other analgesic responses

This section summarizes studies that indicate that analgesia

elicited by a wide range of peptides and transmitters can

alternatively and respectively be sensitive (Section 3.4.1) or

insensitive (Section 3.4.2) to opioid manipulations using

agonists, antagonists and transgenic knockouts.

3.4.1. Opioid-sensitive analgesic responsesA meta-analysis [1042] reviews the ability of placebo admin-

istration to decrease self-report of pain, and the ability of a

blind injection of naloxone to reverse placebo-induced

analgesia. Synergistic analgesic interactions were observed

between the CB agonist, CP55940 and morphine on the hot-

plate and tail-flick tests, whereas additive interactions were

observed between morphine and the alpha-2-adrenoceptor

agonist, dexmedetomidine [1181]. Ultra-low naltrexone doses

enhanced the analgesic effect of the CB-1 agonist, WIN55212-2

[911]. The analgesic actions of the CB-2 agonist, AM1241 in

thermal tests of the hindpaw were blocked by naloxone or

BEND anti-serum pretreatment, and failed to occur in either

MOR KO or CB-2 KO mice. AM1241 stimulated BEND release

from skin tissue and plantar BEND produced analgesia, effects

blocked by a CB-2 antagonist [526].

AS directed against c-Fos reduced the tonic, but not the

phasic aspect of formalin-induced nociception, and decreased

immunoreactivity for DYN and Fos in the dorsal horn [1366].

OXY produced analgesia by inhibiting trigemino-hypoglossal

reflexes in rats, an effect blocked by mu and kappa, but not

delta opioid receptor antagonists [1386]. Intra-arcuate treat-

ment with galanin increased hindpaw withdrawal latency that

was blocked by arcuate pretreatment with general and mu, but

not kappa or delta opioid antagonists. In turn arcuate

pretreatment with the galanin antagonist, galantide reduced

systemic morphine analgesia [1136]; a similar pattern of

effects was observed for intrathecal injections [1311]. Pre-pro-

Enk KO mice displayed significant reductions in the analgesic

and CPP properties of nicotine, in withdrawal signs induced by

mecamylamine in nicotine-dependent animals, and in nico-

tine-induced enhancements of NAC extracellular DA [89].

Exposure to cigarette smoke produced analgesia that was

subject to rapid tolerance, and blocked by both mecamylamine

and naltrexone [1085]. Naloxone blocks nicotine-induced

analgesia as well as precipitating the nicotine abstinence

syndrome in mice [96].

Central SP-induced analgesia on thermal and mechanical

tests was significantly reduced in morphine-tolerant rats [300].

Ezlopitant, a tachykinin NK-1 antagonist, and resiniferatoxin,

a vanilloid VR1 receptor modulator, like morphine block the

nociceptive behaviors induced by 4beta-phorbol-12-myris-

tate-13-acetate [1203]. The mammalian tachikinin peptide,

hemokinin-1 produced a naloxone-sensitive and NK1-sensi-

tive analgesia at high doses, and an ORL-1 antagonist-

sensitive hyperalgesia at low doses [371]. The weak analgesic

effect induced by the hypno-sedative drug, zolpidem was

antagonized by naloxone and yohimbine [935]. The NSAIDs,

naproxen, piroxicam, metamizol, diclofenac and ketoprofen

all produced analgesia on the acetic acid writhing test that

displayed spinal synergy with morphine [805]. The COX-2

inhibitors, parecoxib, meloxicam and nimesulide all displayed

analgesic synergy with intrathecal morphine [936]. Intrathecal

administration of the COX inhibitor, ketorolac paired with

morphine diminish tactile hypersensitivity after surgery in

rats [772]. Paroxetine produced significant naloxone-reversible

analgesia on the acetic acid writhing test in mice, an effect

potentiated by 5-HT-2 antagonists and blocked by 5-HT-3

antagonists [588]. Intrathecal administration of the cyclin-

dependent kinase 5 inhibitor, roscovitine produced analgesia

on the formalin test that was partially blocked by naloxone

[1250]. Intrathecal morphine synergistically enhanced the

anti-allodynic effect of the adenosine A1 agonist, R-PIA in a rat

model of nerve ligation injury using tactile stimuli [524]. The

serotonergic and NE reuptake inhibitor, duloxetine, like

morphine, produced analgesia on the mouse acetic acid

writhing test, and was anti-hyperalgesic and anti-allodynic

on the carrageenan and capsaicin models in rats [556].

Systemic and intrathecal administration of the P2X3/P2X2/3

antagonist, A-317491 produced naloxone-sensitive inhibition

of the CFA model of thermal hyperalgesia and the second

phase of formalin pain, but not the neuropathic allodynia

induced by spinal nerve ligation [788].

alpha- and beta-Amyrin, a triterpene mixture isolated from

Protium heptaphyllum, reversed capsaicin-induced paw-licking

behavior in a naloxone-reversible fashion [878], but produced

naloxone-insensitive analgesia on the formalin test [895].

Heating the aqueous extract of Corchorous oliorius L. leaves

produced peripheral and central analgesia on the hot-plate

and abdominal constriction tests with the peripheral effect

sensitive to naloxone [1340]. The essential oil of Alpinia

zerumbet produced naloxone-reversible analgesia on the acetic

acid writhing, hot-plate and formalin tests [269]. The analgesic

effect of thiophene and its furan derivatives on the tail

withdrawal test was partially blocked by naloxone and Ach

antagonists [419]. The analgesic effects of the two enantio-

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3411

mers of meptazinol appear to share opiate effects based on

structure superpositions [689]. Agmatine analgesia was

blocked by opioid, serotonin, alpha-2-adrenergic antagonism

or inactivation [1038]. Central, but not spinal administration of

(+)-matrine or (+)-allomatrine produced analgesia that was

blocked by spinal, but not supraspinal administration of a DYN

antiserum [496]. A novel monoterpene alkaloid, incarvillateine

elicited analgesia that was blocked by mu and kappa, but not

delta opioid antagonists; an adenosine antagonist was also

effective [209]. Huwentoxin-1, a selective N-type Ca2+ channel

blocker had a slower onset, but a longer time course of action

than morphine following intrathecal administration on the

formalin test [197]. Zhitong capsule administration elicited

analgesia in an adjuvant arthritic rat model while increasing

hypothalamic BEND and serum superoxide dismutase and

decreasing serum lipid peroxides [719].

Low-intensity exercise elicits an anti-hyperalgesic effect on

chronic muscle pain in a naloxone-sensitive manner [80].

Electroacupuncture anti-hyperalgesia in a CFA model of

inflammatory pain was blocked by pretreatment with

Derm-sap, a selective toxin of MOR-containing neurons

[1360]. Electroacupuncture of the ST-36 acupoint produced

naloxone-sensitive analgesia. Electroacupuncture diminished

systemic and intrathecal morphine analgesia, but not

hyperthermia in a manner inversely proportional to the time

intervals between stimulation and morphine injection [376].

Asynchronous acupuncture produced greater analgesia than

synchronous acupuncture; asynchronous acupuncture was

selectively blocked by MOR antagonism and endomorphin-2

antisera, and selectively released endomorphin-2. Both

asynchronous and synchronous acupuncture were blocked

by kappa antagonism, by DYN anti-sera, and both released

DYN [1265]. Acupressure at an acupoint, but not at a placebo

point increased rat tail-flick latencies in a naloxone-reversible

manner [1197]. Daily magnetic field shielding produces

naloxone-sensitive analgesia in mice [950]. Laser therapy

increased pain thresholds in inflamed rat paws, and decreased

BEND-induced inflammation increases in lymphocytes [647].

3.4.2. Opioid-insensitive analgesic responsesTwo ligands of GPR7, neuropeptide W-23 and neuropeptide B,

decrease formalin pain and reduce mechanical allodynia, but

not thermal hyperalgesia induced by paw carrageenan

injections in a naloxone-insensitive manner [1314]. Bumeta-

nide, piretanide and furosemide, all Na(+)–K(+)–2Cl(�) cotran-

sporter inhibitors produced naloxone-insensitive analgesia on

phases 1 and 2 of the formalin test following local or

intrathecal administration [433]. The anti-allodynic action of

Xen2174, a structural analogue of a chi-conopeptide isolated

from a marine cone snail was more effective than morphine

on the chronic constriction injury of the sciatic nerve and the

L5/L6 nerve injury models [857]. Anti-hyperalgesia induced by

the CB-2 receptor agonist, GW405833, in inflammatory and

neuropathic models was naltrexone-insensitive and absent in

CB2 KO mice [1284]. Naloxone failed to alter the enhancement

of wind up by pairing adenosine A1 receptor agonists with

carrageenan-related inflammation in spinalized rats [969]. The

ability of haloperidol and some of its metabolites to inhibit

both phases of formalin-induced pain was unaffected by

naloxone pretreatment [177]. The NMDA receptor channel

blockers, memantine and neramexane, does not display

synergistic interactions with morphine or clonidine in rats

with nerve injury-induced tactile allodynia [752]. Bicuculline

administered into the ventrolateral PAG produced analgesia

irrespective of prior morphine treatment, and elicited

increases in locomotor activity, not morphine-like immobility

[819]. Activation of nicotinic Ach receptors with ABT-594

produced an anti-allodynic response to mechanical stimuli in

a neuropathic pain model that was insensitive to naloxone,

but blocked by mecamylamine [735]. Choline increased hot-

plate latencies and blocked anti-inflammatory pain in rats,

effects blocked by methyllycaconitine citrate, alpha-bungar-

otoxin or atropine, but not by meacmylamine or naloxone,

suggestive of a role for alpha7 nicotinic receptors [1263]. The 5-

HT-1A agonist, F13640 inhibited nociceptive responses, wind-

up and afterdischarges in spinal neurons and withdrawal

reflexes that were blocked by WAY100635, but not naloxone.

Fentanyl’s similar actions were blocked by naloxone, but not

by WAY100635 [1328]. CRF reduces pressure, but not heat pain

in humans without changes in BEND levels in humans [776].

The antibiotics, ciprofloxacin and gentamicin, produced

naloxone-insensitive analgesic effects with the former, but

not the latter displaying additive analgesic effects with

intrathecal morphine [732]. Trimetazidine, an anti-ischemic

compound, inhibited acetic acid-induced writhing responses

in a naloxone-insensitive manner [2]. Hemopressin, derived

from the alpha-chain of hemoglobins, produced a naloxone-

insensitive anti-hyperalgesia in animals treated with either

carageenin or bradykinin [251]. Analgesia induced by (+)-

matrine on the hot-plate test was blocked by muscarinic

cholinergic agents, but not by naloxone, and (+)-matrine had

no affinity for mu, delta or kappa receptors [1323]. Both a bee

venom subfraction and melittin, one of its major constituents,

produced a naloxone-insensitive and alpha-2-adrenergic

antagonist-sensitive analgesia on the mouse acetic acid

writhing test while suppressing visceral pain-induced c-Fos

activation in the spinal cord [646]. A Kampo medicine,

shakuyakukanzoto, produced analgesia in diabetic mice that

was insensitive to mu, delta or kappa antagonists [882].

Extracts from the Amazonian vine, Uncaria tomentosa produces

analgesia on the formalin test that was blocked by the 5-HT-2

antagonist, ketanserin, but not naltrexone [558]. Nigella sativa

polyphenols produced a naloxone-insensitive analgesia on the

acetic acid writhing and formalin tests, but was ineffective or

less effective on the tail-flick, croton oil edema or carageenan

edema tests [405]. Analgesia induced by an extract of the

leaves, but not roots of the Brazilian plant, Nidularium procerum

was observed on the mouse writhing and rat bradykinin-

induced hyperalgesia tests, effects insensitive to naloxone

pretreatment [22]. Analgesia on the formalin and capsaicin

tests induced by the leaf essential oil from Croton sonderianus

was naloxone-insensitive [1039]. Naloxone insensitivity was

observed for analgesia on the abdominal constriction model

following administration of Channa striatus fillet extract [1341].

4. Stress and social status

This section will examine the phenomenon of stress-induced

analgesia (Section 4.1), emotional responses in opioid-

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83412

mediated behaviors (Section 4.2), and opioid involvement in

stress response regulation (Section 4.3).

4.1. Stress-induced analgesia

A review [485] summarizes the antagonistic interactions

between CCK and opioids in stress-induced analgesia as well

as in memory and anxiety function. A second review [95]

summarizes the analgesic effects of sucrose in the rat and

human. Analgesia induced by chronic sucrose intake was

reduced by naloxone, naloxonazine and by the serotonin

antagonists, methysergide and ketanserin [980]. The artificial

sweetener, aspartame produced synergistic effects with

morphine and pentazocine on the acetic acid writhing test

as well as producing analgesia and anti-hyperalgesia [1064].

Experience of social defeat enhanced the nociceptive effects of

formalin treatment and increased CCK in the frontal cortex,

effects blocked by the CCK-B receptor antagonist, CI-988 and

morphine [29]. An enriched environment made rats more

sensitive to the analgesic effects of buprenorphine, butor-

phanol and nalbuphine, but not morphine or levorphanol.

Pairing butorphanol or nalbuphine with morphine respec-

tively reduced and enhanced analgesia in animals raised in

isolated and environmentally enriched settings [1103]. Acute

noise stress produced a naloxone-sensitive analgesia with

increased corticosterone, and decreased 5-HT-2 and MOR

receptors in the frontal cortex of both male and female mice

[1239]. Chronic, but not acute restraint stress over 40 days

increased TMJ formalin responses, and decreased the sub-

sequent effectiveness of morphine analgesia [393]. Whereas

acute swim stress produced a naloxone-insensitive analgesia

on the formalin test, swim stress delivered over 2–3 days

produced tolerance that was cross-tolerant with morphine

and indeed enhanced morphine tolerance on this measure

[344]. Analgesia elicited by hemorhagic shock stress was

unaffected by naloxone [377].

Placebo-induced analgesia increased over time in irritable

bowel syndrome patients that was associated with desire and

expectation, but in a naloxone-insensitive manner [1225].

Post-operative music delivered to patients undergoing hernia

repair surgery reduced plasma cortisol and reduced morphine

consumption and pain 1 h after surgery [863]. Spinal surgery

patients exposed to sunlight displayed less post-surgical

stress, marginally less pain, took less analgesic medication

and less pain medication costs [1240].

4.2. Emotional responses in opioid-mediated behaviors

A factor analysis revealed that attack behavior in non-isolated

male mice in a neutral area covaried with low BEND and ACTH

concentrations [1012]. Brain stimulation reward thresholds for

lateral hypothalamic self-stimulation were 50% higher in DA

D2 receptor-KO mice, and this group failed to display

potentiations in this response following morphine [318].

Defeat increased MOR mRNA expression in the VTA, but not

SN, and VTA DAMGO increased locomotor activity in defeat

stress relative to controls [862]. Using measures of traditional

stress in mice, repeated spontaneous morphine withdrawal

represented a mild stress load, whereas repeated naloxone-

precipitated withdrawal produced clear chronic stress fea-

tures equal to restraint or exposure to a rat [1354]. Whereas

local naloxonazine injections into the mesencephalic tectum

increased escape thresholds induced by local electrical

stimulation, naltrexone or naloxonazine administered into

the SN, pars reticulata increased defensive thresholds elicited

by electrical stimulation of the dorsolateral PAG and deep

layers of the superior colliculus [990]. MOR KO mice showed

normal fear acquisition, but failed to display conditioning to

fear when acquisition was conducted across 5 days [1035].

Extinction to a fearful auditory conditioned stimulus was

retarded by ventrolateral PAG infusions of mu opioid

antagonists and a cAMP analog, but not by delta or kappa

antagonists, activators of PKA or a MAPK inhibitor [793].

Administration of the Enk enzyme inhibitor, RB101(S) into the

ventrolateral PAG, but not surrounding areas facilitated

extinction from a fearful auditory conditioned stimulus

[791]. Indeed, naloxone-precipitated withdrawal was

enhanced 1 day after restraint stress in a NMDA-sensitive

and a glucocorticoid-sensitive fashion, but reduced 7 days

after restraint stress [792]. The NOR agonist, Ro64–6198

increased punished responding in a rat conditioned lick

suppression test that was blocked by J11397, but not naloxone,

reduced isolation-induced vocalizations in rodent pups, and

increased punished responding in the mouse Geller–Seifter

test in wild-type but not NOR KO mice [1224].

4.3. Opioid involvement in stress response regulation

A review [187] indicates that BEND is a principal effector of the

stress system involving CRF, VP, AMSH, glucorticoids, and

catecholamines. A second review [989] summarizes evidence

implicating endogenous opioids and MOR in the interface

between physical and emotional stress regulation. Another

review [1189] indicates that both ACTH and POMC peptides

help regulate pigmentation in the hair follicle and epidermis,

an important stress response element of the skin’s sensing

apparatus. POMC is processed in the skin that also produces

the prohormone convertases PC1, PC2 and 7B2 protein [1190].

Previous morphine exposure potentiates restraint stress-

induced anxiety while reducing stress-induced pressor

responses [107]. Whereas morphine and a H2 receptor

antagonist produced anxiolytic effects on the elevated plus

maze, histamine and a H1 receptor antagonist produced

anxiogenic effects. No interaction was observed between

opioid and histaminergic systems [1349]. Maternal morphine

exposure increases anxiety responses on the elevated plus

maze and novel environment tests in adult female offspring,

and enhances morphine-induced behavioral sensitization in

both adult male and female offspring [146]. Pre-natal

morphine blocked TH, adrenal epinephrine and phenyletha-

nolanine-N-methyltransferase mRNA expression following

ether inhalation that was accompanied by increased hypotha-

lamic and hippocapmpal serotonin and its metabolite [648].

Morphine exposure over 7 days increased by 2.5-fold the

pituitary-adrenocorotical response to mild stress in juvenile

rats relative to adult rats [864]. Repeated restraint stress over

40 days significantly reduced opioid receptor density in

cortex, hippocampus and spinal cord [259]. Acute, but not

chronic stress increases endogenous morphine found in the

hemolymph and nerve cord of the American lobster [170].

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3413

Exposing catfish to low water levels increased plasma POMC

within 15 min after stress onset and after 1 h of reinstatement

of water levels [574]. KOR B and C, but not MOR mRNA levels

were reduced in the VTA, but not NAC in male mice that were

repeatedly winners, but not losers in aggressive episodes

[415]. NTI and the delta-2 antagonist, naltriben, but not the

delta-1 antagonist, 7-benzylidenenaltrexone decreased the

number of visits to the open arms of the elevated plus maze,

effects reversed by the delta agonist, SNC-80. Plasma

corticosterone was increased by NTI in the elevated plus

maze, and this effect was blocked by SNC-80 as well [1024].

The anxiogenic effects of high nicotine doses on the elevated

plus maze were enhanced by NTI, but not BFNA or NBNI,

whereas the anxiolytic effects of low nicotine doses on the

same measure were abolished by BFNA, but not NTI or NBNI

[57]. Nicotine-induced anxiogenesis in the plus maze and

holeboard tests were unaffected by kappa agonists and

antagonists, but NBNI blocked nicotine-induced increases in

corticosterone levels [761]. Whereas DAMGO attenuated

separation distress vocalizations in young domestic fowl,

no other general or selective mu, delta or kappa or NOR

agonist or antagonist altered these responses [1269]. Cat odor

abolished morphine-induced increases in exploratory beha-

vior in a novel environment, and increased POMC and

MOR gene expression in brain structures associated with

anxiety and motivation [37]. Grower pigs immunized against

ACTH and exposed to restraint stress displayed suppressed

cortisol and increased BEND without changes in vocalizations

[667]. Relative rates of acetylated BEND and AMSH release

following CRF stimulation in the common carp in vitro

match plasma level changes in vivo [1218]. U50488H reduced

prepulse inhibition of the acoustic startle reflex, an effect

blocked by NBNI and clozapine, but not by haloperidol [120].

5. Tolerance and dependence

The most-often studied variables in the functional analysis of

opioid-mediated responses next to analgesic processes are the

underlying neurobiological roles of tolerance and dependence.

Developments will be reviewed for animal models in tolerance

(Section 5.1), and animal models in dependence and with-

drawal responses (Section 5.2).

5.1. Animal models in tolerance

This section will be divided into the following sub-sections:

(i) cellular effects on morphine tolerance, (ii) organismic

effects on morphine tolerance, (iii) opioid effects on morphine

tolerance, (iv) peptide-transmitter effects on morphine toler-

ance, and (v) other forms of opioid tolerance.

5.1.1. Cellular effects on morphine toleranceA review [23] summarizes the transcriptional regulation of

MOR trafficking (GRK2, beta-arrestin-2) and altered expression

of dopamine, NMDA, GABA-A and alpha(2A)-adrenoceptor

receptors following repeated morphine treatment. A second

review [52] studied the roles of MOR desensitization and

trafficking as well as changes in other proteins following

opioid tolerance and dependence. A third review [891]

summarizes evidence indicating that tolerance may be related

to a hyperalgesic state resulting from opiate exposure that

increases pain facilitation mechanisms by CCK in the RVM

that leads to up-regulation of spinal DYN and increased CGRP

and SP expression in the DRG. A fourth review [1306] evaluated

Regulator of G-protein signaling proteins in modulating opioid

signaling and tolerance mechanisms. A fifth review [1387]

summarizes the roles of opioid receptor internalization and

beta-arrestins in the development of tolerance.

Central morphine administration failed to alter MOR

immunoreactivity, but co-precipitation of G-alpha subunits

with MOR was reduced while G-alpha subunits and RGS9-2

proteins were increased. RGS9-2 KO mice failed to display

morphine tolerance even though morphine’s ability to

activate G-proteins was intact [398]. Long-term morphine

treatment enhances proteosome-dependent degradation of

G-beta in human neuroblastoma SH-SY5Y cells that correlates

with adenylate cyclase sensitization [827]. Chronic morphine

tolerance could be reversed by chronic formalin-induced pain

with G-alpha i/o expression increased by chronic pain, but not

chronic morphine, and G-beta expression increased by

chronic morphine, but not chronic pain [547]. Chronic

morphine significantly increases PKA activity in the lumbar

spinal cord, but not the brain of tolerant mice [254]. In both

drug-naı̈ve and morphine-tolerant mice, peptide fragments of

the PKA inhibitor, PKI inhibited cytosolic PKA activity in

lumbar spinal cord and thalamus to the same degree,

indicating reversal of morphine tolerance by PKA inhibition

[253]. Chronic morphine acts through a PKC-gamma-G(beta)-

adenylyl cyclase complex to augment phosphorylation of

G(beta) and G(betagamma) stimulatory adenylyl cyclase

signaling [183]. Up-regulation of glucocorticoid receptors,

the NMDA NR1 subunit and PKCgamma by chronic intrathecal

morphine are diminished by the glucorticoid receptor

antagonist, RU38486, a glucocorticoid AS, a PKA inhibitor,

H89 or a CREB AS [699]. Similarly, up-regulation of spinal CB-1

and CB-2 cannabinoid receptors by chronic intrathecal

morphine is reduced by co-administration of RU38486 [697].

Chronic morphine reduced the abundance of plasma mem-

brane-associated MOR in epinephrine-containing dendrites in

the rostral VLM, appearing only in distal dendrites [306].

Central morphine tolerance occurred at MOR, but did not

disrupt co-precipitation of MOR-DOR complexes. Morphine

reduced co-precipitation of G-alpha i/o/z subunits with MOR

and diminished RGS9-2 with MOR [400]. Both acute and

chronic morphine increase N-acetyltransferase mRNA

expression in the pineal gland and increase CREB phosphor-

ylation [207]. Chronic morphine increased calcium/calmodu-

lin-dependent protein kinase IV and pCREB in the

hippocampal CA3 region, decreased both in the C/P, and

decreased the former in the basolateral amydala and primary

somatosensory cortex [853]. Acute and chronic morphine

respectively inhibit and activate adenylyl cyclase I and VIII

activity through a pertussis toxin-sensitive mechanism with

both responses blocked by G-betagamma scavengers [1123].

Sustained morphine infusion produced hyperalgesia as well

as increased SP and NK-1 receptor expression in the spinal

cord, capsaicin-induced SP release in vitro and internalization

of NK-1 receptors in the superficial and deep layers of the

spinal cord, effects blocked by NK-1 antagonism and absent in

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83414

NK-1 KO mice [598]. Chronic morphine increases mRNA

of RGS-7, RGS9-2, RGS11 and Gbeta5 in the striatum,

thalamus, PAG and cortex [725]. Chronic morphine treatment

decreased the magnitude of DAMGO-induced inhibition of

voltage-gated Ca2+ currents and of Menk-induced inhibition of

GIRK currents in isolated mouse PAG neurons [48]. The

activity of neuronal NOS and KOR expression within the PAG

provide intracellular control over the development of mor-

phine tolerance and dependence [490]. Repeated, but not

single treatment with morphine increased the deltaFosB

transcription factor in the NAC, striatum and frontal cortex,

with the first two effects blocked by D1 DA antagonism.

Chronic heroin produced significant effects only in the

striatum [831]. Morphine tolerance increases presynaptic

glutamate release in mu receptor-containing NRM neurons

through up-regulation of both cAMP/PKA and PKC pathways

[98]. Both chronic morphine tolerance and withdrawal

produce up-regulation of PKC and Ca(2+)/calmodulin-inde-

pendent kinase II which engages ERK inhibition [102]. An

endogenous regulator of G-protein signaling proteins reduces

MOR desensitization and down-regulation as well as adenylyl

cyclase tolerance in C6 cells [224]. Chronic morphine

enhances MOR co-immunoprecipitates with G-s-alpha, but

diminishes the co-immunoprecipitation of MOR with G-i-

alpha [182].

5.1.2. Organismic effects on morphine toleranceA review [599] indicates that sustained exposure to morphine

results in paradoxical pain that is modulated by SP NK-1

antagonists, CGRP receptor antagonists, NOS inhibitors,

calcium channel blockers, COX and PKC inhibitors, NMDA

and AMPA antagonists, and CCK antagonists. Morphine

tolerance, defined as a 75% reduction in analgesic magnitude

of the initial treatment displayed age-related increases in

the number of treatments to attain that criterion [1262].

Assessment of morphine tolerance in mice revealed non-

identical tolerance and dependence development following

chronic morphine administered ventricularly, intrathecally,

intravenously and through pellet implantation [680]. Mor-

phine tolerance was much greater following repeated micro-

injections into the ventrolateral PAG (64% decrease) relative

to the RVM (36% decrease); increasing the number of

RVM injections did not enhance tolerance development

[820]. Intermittent morphine dosing prolongs analgesic

tolerance elicited from the ventrolateral PAG [821]. Behavioral

tolerance in which analgesic testing is performed after each

systemic or central morphine administration can be over-

come by a high (20 mg/kg) morphine dose; pharmacological

tolerance is insensitive to this manipulation [655]. A second

morphine injection 1 week after an initial morphine injection

produced short-term analgesic tolerance on the tail-flick test,

but failed to affect anti-hypergesia on the carrageenan-

induced paw withdrawal test [512]. In an operant paradigm

using pigeons, changes in the fixed-ratio value or absolute

output of the reinforcer determined the degree of morphine

tolerance better than the unit price of the reinforcer [518].

Both systemic and environmental ethanol administration

enhanced morphine analgesia in naı̈ve mice, and produced

leftward shifts in morphine analgesia in morphine-tolerant

mice [927].

5.1.3. Opioid effects on morphine toleranceA mu-opioid receptor knock-in mouse displayed analgesic

responses to naltrexone and a failure to display analgesic

tolerance to morphine and naltrexone, effects blocked by the

delta agonist, SNC-80 [1015]. mu-delta Antagonist series

ligands that contain different length spacers were active

analgesics. Chronic central studies revealed that ligands that

had a spacer that was 16 atoms or longer produced less

dependence, whereas ligands with a spacer greater than 19

atoms showed suppression of physical dependence and

tolerance [257]. Chronic morphine in producing tolerance,

elicited increased expression of MOR in laminae I and II of the

dorsal horn and NOR in the dorsal horn and around the central

canal [978]. A cocktail of morphine and a small dose of

methadone that facilitates MOR endocytosis reduced mor-

phine tolerance and dependence in morphine-treated ani-

mals, and did not promote morphine dependence itself [483].

Ultra-low doses of naltrexone suppress both opioid tolerance

and dependence, and attenuated chronic morphine-induced

G-s coupling and G-betagamma signaling to adenylyl cycalse

[1256]. Naltrexone administration into the ventrolateral PAG

blocked morphine analgesia and attenuated the development

of systemic morphine tolerance. Whereas muscimol infusion

into the RVM blocked ventrolateral PAG morphine analgesia, it

failed to affect morphine tolerance [656]. Prolonged morphine

translocated DOR from intracellular to subplasmalemmal and

membrane compartments of the NAC and striatum, but not

frontal cortex [731]. Combinations of morphine with opioid

drugs with high endocytotic effacies did not facilitate

morphine-mediated endocytosis, but decreased receptor

endocytosis mediated by these drugs. Endocytotic potencies

of opioid drugs are negatively correlated with receptor

desensitization and opioid tolerance presumably by inducing

fast receptor reactivation and recycling to counteract the

tolerant state [612].

5.1.4. Peptide-transmitter effects on morphine toleranceIn the presence of morphine, NO increased the constitutive

activation of the MOR and reduced the ability of morphine to

activate the mu-opioid G-protein-coupled receptor in a time

course consistent with the development of morphine toler-

ance [488]. Inhibition of neuronal NOS with 7-nitroindazole

attenuated the development of morphine tolerance, and

blocked tolerance to Menk inhibition of LC neurons [1037].

Desensitization of morphine responses by three consecutive

injections is blunted by blockers of Galpha-z, but not Galpha-i2

subunits. In turn, central Galpha-i2 subunit administration

potentiates morphine analgesia and blocks acute tolerance,

whereas Galpha-z subunit administration induces more rapid

desensitization [1033]. Chronic morphine exposure induces

cAMP and PKA up-regulation of neuronal spinal glucocoticoid

receptors; AS or antagonists against these receptors in turn

exacerbate morphine tolerance [698]. Inhibitors of cAMP or

PKA attenuated the development of intrathecal morphine

tolerance and prevented the down-regulation of spinal

glutamate transporters [696]. Intrathecal L-type Ca2+ channel

blockade blocked opioid-induced sensory hypersensitivity and

chronic morphine-induced tolerance [295]. The Ca2+ channel

blocker, nifedipine prevented the development of morphine

tolerance to a greater degree in adrenalectomized relative to

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3415

normal rats with the former effect blocked by corticosterone

replacement therapy [329]. The inhibitor of glutamate carbox-

ipeptidase II, 2-MPPA prevented the development of morphine

tolerance without affecting morphine analgesia or the devel-

opment of morphine dependence. In withdrawn animals, 2-

MPPA enhanced jumping and teeth chattering, and attenuated

chewing and ptosis in a mGluR II antagonist-sensitive manner

[630]. However, systemic administration of the phosphodies-

terase inhibitor, propentofylline failed to attenuate the

development of morphine tolerance in non-injured rodents

[1082].

The spinal metabotropic glutamate receptor 5 inhibitor,

MPEP, blocked morphine analgesia, presumably by blocking

morphine-induced increases in dorsal horn mGlu5 receptors

[846]. Dexamethasone cotreatment attenuated the develop-

ment of morphine tolerance by inhibiting chronic morphine-

induced increases in CSF glutamate and aspartate and

preventing the down-regulation of glial glutamate transpor-

ters, but not the neuronal glutamate transporter carrier [1278].

An AS directed against the NMDA subunit NMDAR1 reduced

morphine tolerance, and attenuated NMDA-induced nocicep-

tion and hyperalgesia [1077]. The combined NMDA receptor/

glycine(B) site antagonists, MRZ2/576 and MRZ2/596, and to a

lesser degree MDL105519 dose-dependently attenuated the

development of morphine tolerance in Swiss and C57/Bl mice

[260]. Dizocilpine, an NMDA receptor antagonist, decreased

morphine tolerance per se as well as the reappearance of

morphine analgesia in morphine-tolerant animals placed in a

different context [840]. The ability of intrathecal gabapentin to

attenuate morphine tolerance is associated with suppression

of morphine-evoked excitatory amino acid release in the

spinal cord [700]. Intrathecal melanocortin receptor antago-

nists, SHU9119 or JKC-363 repeatedly co-administered with

morphine blocked morphine tolerance, and a single injection

of the melanocortin antagonist restored morphine analgesia

in morphine tolerant rats [1122]. The ability of midazolam to

inhibit the development of acute and chronic morphine

tolerance on the formalin test in mice was reversed by

intrathecal injection of the NO precursor, L-arginine. Formalin

increased inducible and neuronal NOS protein levels in the

spinal cord that is inhibited by midazolam, and midazolam

decreased formalin-induced expression of Fos in the mor-

phine-tolerant spinal cord [153]. The endothelin A receptor

antagonist, BQ123 reversed morphine tolerance, enhanced

morphine analgesia and increased G-protein activation in

morphine-tolerant mice [92].

5.1.5. Other forms of opioid toleranceThe delta agonist, SNC80 displayed rapid tolerance to its

convulsive and locomotor-stimulating effects, but not to its

antidepressant-like effects; this was paralleled by site-specfic

tolerance using 50-O-(3-[35S]thio)triphosphate binding [559].

Chronic etorphine infusions produced down-regulatation of

MOR density, dynamin-2 proteins and mRNA abundance in

mouse spinal cord [1358]. An alkaloid from the Thai medicinal

herb, Mitragyna speciosa, 7-hydroxymitragynine, produces

analgesia and tolerance that is sensitive to opioid antagonists

and cross-tolerant with morphine, and when administered

chronically, is sensitive to naloxone-precipitated withdrawal

[782].

5.2. Animal models in dependence and withdrawalresponses

This section will be divided into the following sub-sections:

(i) cellular effects on morphine dependence and withdrawal,

(ii) organismic effects on morphine dependence and with-

drawal, (iii) opioid effects on morphine dependence and

withdrawal, (iv) peptide-transmitter effects on morphine

dependence and withdrawal, and (v) other forms of opioid

dependence and withdrawal.

5.2.1. Cellular effects on morphine dependence andwithdrawal responsesA review [842] examines the usefulness of NMDA receptor

antagonism and its associated protein kinase in the NAC for

treatment for psychological dependence on morphine. Mor-

phine dependence resulted in marked reductions in cellular

proliferation in neural phenotypes in the dentate gyrus and

CA3 regions of the hippocampus accompanied by expression

levels of the polysialylated form of neural cell adhesion

molecule, effects that returned to normal after 2 weeks of

withdrawal [564]. Hippocampal gating is disrupted in a

haloperidol-sensitive manner during development of mor-

phine dependence, but there are enhancements in hippocam-

pal gating by the fifth day of opiate withdrawal [1372].

Morphine dependence also reduced response modulation

and a longer time course of responses in primary visual

cortical cells in cats [482]. Morphine-dependent monkeys

administered morphine into the orbito-frontal and dorsal–

lateral prefrontal cortex displayed decreases in all EEG power

bands [714]. The ability of agmatine to inhibit cellular

morphine dependence is mediated by imidazoline receptor

anti-sera-selected protein [1299]. Activation of the spinal ERK

pathway by chronic morphine and by naloxone-precipitated

withdrawal were blocked by the non-competitive NMDA

antagonist, MK-801 or the PKC inhibitor, chelerythrine [154].

Compression of the hindpaw produced pain responses and

NK1 receptor internalization in lamina I dorsal horn neurons,

effects blocked by acute morphine and intrathecal morphine

infusions for 1 day. Morphine infusions over 5 days failed to

affect escape or internalization whereas naloxone-precipi-

tated withdrawal actually increased internalization with the

latter effect blocked by a NK1 receptor antagonist [448].

Naloxone-precipitated morphine withdrawal produces up-

regulation of PKA, PKC-delta and PKC-zeta, and down-

regulation of PKC-alpha in the heart [179]. Chronic morphine

withdrawal decreased alpha-synuclein mRNA in the basolat-

eral amygdala, dorsal striatum, NAC and VTA, but increased

alpha-synuclein protein in the amygdala, striatum and NAC

[1380]. Proteonomic analysis of morphine-dependent rat

brains revealed increased phosphotyrosyl protein spots in

the frontal cortex indicative of changes in tyrosine phosphor-

ylation [597]. Spontaneous and naloxone-precipitated mor-

phine withdrawal decrease spine density in second order

dendritic trunks where afferents converge in the NAC shell, but

not NAC core regions; chronic morphine per se failed to induce

such changes [1121]. Opioid withdrawal in vitro induced an

opioid-sensitive cation current mediated by the GABA trans-

porter-1 and required PKA activation; inhibition of these two

events prevented withdrawal-induced hyperexcitation of PAG

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83416

neurons [49]. Naloxone-precipitated morphine withdrawal

increased Fos and PKA and TH immunoreactivity in the

NTS/VLM and PVN; TH immunoreactivity was respectively

increased and decreased in the NTS/VLM and PVN, effects

reversed by pretreatment with a PKA inhibitor [82]. Morphine

dependence and naloxone-precipitated withdrawal produce

very different gene profiles according to DNA microarray

analyses of the LC and VTA [786]. Naloxone increased OXY, but

not VP neuron post-spike excitability in the SON to a greater

degree in morphine-tolerant than morphine-naı̈ve rats by

reducing transient outward rectification and after-hyperpo-

larization properties [136]. The beta-carboline, noharman, and

the imidazoline I2 ligand, LSL60101, prevented increased

cortical and hippocampal DOPA synthesis and withdrawal

signs induced by naloxone-precipitated withdrawal [804].

5.2.2. Organismic effects on morphine dependence andwithdrawal responsesNaloxone, naltrexone and diprenorphine were more effective

in producing jumping responsdes in morphine-dependent rats

at lower morphine doses than nalorphine and naloxonazine,

but pretreatment with the latter two antagonists could block

naloxone-precipitated jumping responses [1244]. Isolated rats

displayed fewer signs of physical dependence and withdrawal

as well as a less intense conditioned place aversion than

group-housed rats receiving twice a day morphine treatments

[135]. In contrast, previously neutral light-tone stimuli can

produce potentiations of physical signs associated with

morphine dependence and then withdrawal [1051]. Re-

exposure of opiate-dependent rats to stimuli paired with

withdrawal produced c-Fos activation of a different sub-

population of basolateral amygdala neurons than those

activated by acute withdrawal. In contrast, a population of

VTA DA neurons was activated under acute and re-exposure

conditions [369]. Repeated re-exposure of guinea pigs to

morphine dependence and naloxone-precipitated withdrawal

produced progressively sensitized withdrawal responses, but

not locomotor activity changes after the third treatment,

effects accompanied by increased c-Fos in the amygdala,

dorsal striatum, thalamus, VTA and ventrolateral PAG [809].

Morphine withdrawal up-regulated the mRNA levels of the

adenylyl cyclase VI and VII isoforms in the RVM while

enhancing the hyper-polarization-activated current in these

cells [99]. Naltrexone-precipitated withdrawal produced

increased blood pressure, heart rate, reduced tolerance to

colon distension and increased vegetable variables in dogs,

effects ameliorated by the PKC inhibitor, H7 [370]. Naloxone

increased opioid craving, withdrawl signs, but not operant

behavior in physically dependent volunteers. A drug versus

money reinforcement opportunity did not increase opioid

craving [440]. Electroacupuncture decreased naloxone-preci-

pitated morphine withdrawal with this intensity decreasing

amygdala c-Fos expression in freely moving rats, but

increased amygdala c-Fos expression, increased vocalization

and increased corticosterone levels in restrained rats [715].

5.2.3. Opioid effects on morphine dependence andwithdrawal responsesNovel exonic MOR gene polymorphisms, dbSNP rs540825 and

dbSNP rs562859, were not related to opioid dependence [1104].

The kappa antagonist, JDTic decreased wet dog shakes and

facial rubs in morphine-withdrawn rats, but failed to affect

continuous morphine-induced stereotypy and withdrawal-

induced weight loss [166].

5.2.4. Peptide-transmitter effects on morphine dependenceand withdrawal responsesIn a model of acute naloxone-precipitated morphine depen-

dence in the isolated guinea pig ileum, L-NME and guanylate

cyclase inhibition reduced withdrawal symptoms, effects

reversed by L-arginine and NO donors. These withdrawal

effects were also blocked by competitive NMDA antagonism

with AP-5, and reversed with L-glutamate [383]. MPEP and

MTEP, mGlu5 receptor antagonists, attenuate morphine with-

drawal signs and reduce morphine withdrawal-induced

activation of LC neurons [972]. Ionotropic glutamate antagon-

ism with MK-801 or DNQX in the VTA blocked naloxone-

precipitated morphine withdrawal signs except for weight loss

and reduced the withdrawal-induced expression of stable

deltaFosB isoforms in the NAC [1255]. Heterozygous and

homozygous CRF-1 receptor KO mice avoided environmental

cues paired with the early phase of morphine-induced

withdrawal, but showed reliable conditioned place aversions

to the kappa agonist, U50488H [232]. Sub-anesthetic doses of

ketamine or midazolam interfered with the expression of

naloxone-precipitated opiate withdrawal [1131]. The PKC

inhibitor, calphostin blocked morphine withdrawal-induced

increases in c-Fos in the PVN, NTS and VLM, the increased TH

immunoreactivity in the NTS and VLM, and the decreased TH

levels in the PVN [81]. Administration of the D1 DA agonist,

SKF38393 into the LC decreased naloxone-induced morphine

withdrawal signs [291]. Both D1 and D2 receptor antagonists

decreased the expression of naloxone-precipitated morphine

withdrawal signs although striatal and cortical DA and DOPAC

levels were decreased only in withdrawn male mice [288].

Blockade of alpha3beta4 nicotinic receptors with combined

treatment with dextromethorphan, mecamylamine and

bupropion reduced the naloxone-precipitated morphine with-

drawal signs of diarrhea and weight loss [1166]. Whereas

clonidine reduced naltrexone-induced withdrawal signs in

monkeys dependent on the mu opioid, L-alpha-acetylmetha-

dol, cocaine and amphetamine accentuated naltrexone-

induced effects, and haloperidol produced mixed actions

[1055]. The SSRI’s, fluoxetine, clomipramine and citalopram,

attenuated morphine withdrawal symptoms in neonatal rats

passively exposed to morphine [1295]. An adenosine A1

receptor antagonist and NBNI increased the withdrawal

response following acute dermorphin–naloxone combina-

tions, but failed to affect withdrawal in the presence of

CCK-8 [1005]. The CB-1 antagonist, SR141716 also increased

the withdrawal response to naloxone following acute dermor-

phin, but only in the presence of KOR and adenosine A1

antagonism [1006]. Intrathecal treatment with recombinant

interleukin-2 reduced naloxone-precipitated jumping in

dependent mice, and reduced naloxone-precipitated irrita-

tion, diarrhea, weight loss, abnormal posture and salivation in

dependent rats [449]. An ibogaine derivative, 18-methoxycor-

onaridine differentially decreased such signs of naloxone-

precipitated morphine withdrawal as teeth chattering, wet-

dog shakes, burying, diarrhea and weight loss following

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3417

microinjection into the LC, medial habenula or interpedun-

cular nucleus [909]. Opiate-exposed infants displayed greater

interactions, smoother movements, less stress and better

handling when treated with diluted tincture of opium paired

with phenobarbital than the opium tincture alone [240].

5.2.5. Other forms of opioid dependence and withdrawalresponsesButorphanol dependence increased hippocampal KOR gene

expression [1157]. Given that intermittent sugar availability

enhances MOR receptor changes, rats with glucose access

(11.5 h/day, 28 days) and then deprived for 2 weeks, displayed

far greater operant responding for sucrose relative to their

previous behavior and to rats with only operant access to

sugar [44].

6. Learning and memory

Learning and memory effects of endogenous opioid peptides,

their receptors, their agonists and their antagonists, as well as

genetically altered animals continue to be studied extensively.

Recent developments will be reviewed for animal models in

conditioned place preferences (CPP: Section 6.1), conditioned

aversion paradigms (Section 6.2), drug discrimination and

spatial learning (Section 6.3), as well as memory and amnesia

(Section 6.4).

6.1. Opiates and conditioned place preferences (CPP)

The following sections examine opioid CPP (Section 6.1.1) and

non-opioid effects upon opioid CPP (Section 6.1.2).

6.1.1. Opioid CPPWhereas normal rats displayed morphine CPP regarless of

whether the partition between boxes was opaque or clear,

morphine CPP occurred using opaque partitions in animals

with lesions placed in the NAC or amygdala, but not the

fimbria-fornix, and using clear partitions in animals with

lesions placed in the fimbria-fornix, but not amygdala or NAC

[1282]. Morphine pre-exposure enhanced morphine CPP and

reduced morphine-induced taste aversions [1087]. The dose

used in establishing morphine CPP is related to the persistence

of the response after different extinction periods [992].

Morphine CPP was more easily expressed in animals tested

on a 12/12 h or a 6/18 h light/dark cycle than on a 18/6 h light/

dark cycle; abrupt increases or decreases in the light–dark

cycle resulted in poorer morphine CPP induction [1146].

Persistence of morphine and cocaine CPP was maintained

whether the animals were tested intermittently or repeatedly

[1025]. Morphine and cocaine CPP was observed after

controlling for inherent preferences for placement in the

distinctive chambers; thus, morphine CPP would still occur in

a chamber that was less-preferred prior to testing [1004].

Morphine and cocaine CPP was induced at lower doses in

C57BL/6 relative to DBA/2 mice [885]. Morphine CPP that

persisted during morphine tolerance and morphine with-

drawal was accompanied by increased diazepam binding

inhibitor mRNA expression in the CA1 region of the hippo-

campus, VTA, NAC and amygdala [716]. Heroin CPP was

blocked by inactivation of the basolateral nucleus of the

amygdala with combined muscimol and baclofen infusions

[1000], but its CPP-inducing effects in the VTA were poten-

tiated by systemic administration of the benzodiazepine,

alprazolam [1243]. Heroin CPP and locomotor sensitization

were observed in C57BL/6J mice and N(10) congenic B6–129

hybrids, but not in 129X1/sVJ mice, N(3) congenic B6–129

hybrids or F5–8 non-congenic B6–129 hybrids [1142]. CREB

activation within different subregions of the VTA with

different proportions of DA and GABA neurons produce

opposite effects upon CPP of opiate and other drugs of abuse

[881]. Glycyl-glutamine, an endogenous dipeptide synthesized

from BEND blocked the acquisition and expression of

morphine CPP, inhibited the development of morphine

dependence, and suppressed morphine withdrawal symp-

toms without affecting morphine analgesia [175]. The NOR

agonist, Ro64–6198 blocked the acquisition, but not the

expression of morphine CPP. Whereas Ro64–6198 failed to

alter the rate of extinction to morphine CPP, it blocked the

reinstatement of morphine CPP following a priming injection

[1081]. Morphine withdrawal cues elicited the reinstatement

of morphine CPP and increased corticosterone levels [730].

Ultra-low doses of naltrexone blocked morphine CPP as well as

the conditioned aversive responses induced by chronic

morphine or oxycodone [879]. Neither naloxone nor acam-

prosate altered the expression of morphine CPP in isolated or

group-housed rats [492]. Moroever, neither naloxone nor

acamprosate altered the expression of either morphine or

cocaine CPP after repeated testing [493]. Animals that were

more active in the second half of a circular exploratory

corridor subsequently developed morphine CPP more quickly

than low-responding animals [836].

6.1.2. Non-opioid effects on opioid CPPKindling blocked the CPP induced by morphine and cocaine as

well as ethanol-induced aversion [76]. Exposure to low-

frequency electromagnetic fields potentiated morphine CPP

[675]. Inescapable shock potentiated corticosterone responses

to morphine in intact, but not adrenalectomized animals.

Corticosteroid inhibition during shock failed to affect shock-

induced potentiation of morphine CPP, whereas this inhibition

during morphine administration blocked the CPP [282]. CPP

and behavioral locomotor sensitization to morphine or D-

amphetamine were impaired in memory-deficient mice over-

expressing the calcium–calmodulin-dependent phosphatase,

calcineurin [97]. Gene transfer of GLT-1, a glutamate trans-

porter into the NAC reduces CPP induced by morphine and

methamphetamine [374]. Reinstatement of opioid CPP by

morphine was blocked by the NMDA glutamate antagonists,

MK-801 and memantine, but not by the DA antagonists,

SCH23390, raclopride or haloperidol [991]. Cross-reinstate-

ment of an extinguished morphine CPP was produced by

either cocaine or d-amphetamine administration [303]. A NOS

inhibitor, L-NAME and cyclosporin A dose-dependently sup-

pressed the acquisition of morphine CPP [659]. Morphine-

induced CPP was blocked by naloxone and also the DA

antagonists, CGS10746B, SCH23390, raclopride and haloper-

idol [758]. Morphine-induced CPP and its reinstatement were

blocked by depletion of noradrenergic afferents to the medial

prefrontal cortex, an effect that also blocks morphine-induced

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83418

increases of DA in the NAC [1231]. Morphine CPP was dose-

dependently altered by VTA GABA-A agonists (low dose

reduction, high dose increase) relative to GABA-B agonists

and GABA-A antagonists (low dose increase, high dose

decrease) [1022]. Hippocampal CA-1 administration of apo-

morphine, quinpirole, SKF38393 or sulpiride blocked mor-

phine-induced CPP, whereas a similar injection of SCH23390

enhanced morphine-induced CPP [1348].

MS-153, a glutamate transporter activator reduced CPP, but

not locomotor responses induced by morphine, cocaine and

methamphetamine without producing CPP or conditioned

aversions [838]. Agmatine blocked both the expression of CPP

and the reinstatement of morphine CPP after extinction [1275].

Formalin-induced inflammation reduced morphine-induced

CPP as well as morphine-induced increases in DA turnover in

the NAC; the former effect was blocked by the kappa

antagonist, NBNI and the latter effect was blocked by a DYN

antibody administered into the NAC [843]. Within the

basolateral amygdala, the anti-cholinesterase, physostigmine

potentiated morphine CPP in an atropine-sensitive and

mecamylamine-insensitive manner, while nicotine poten-

tiated morphine CPP in a mecamylamine-sensitive, but

atropine-sensitive manner [1346]. DNAzyme, an inhibitor of

mPer1, a circadian clock gene period, reduced morphine CPP in

mice when co-administered with morphine, but not when

administered after morphine [717]. Repeated peripheral

electrical stimulation (2 Hz) enhances spatial memory on

the Morris water maze and produces a moderate CPP, yet

inhibits the expression of morphine-induced CPP [196].

Androgen receptor blockade with flutamide in females

blocked a CPP induced by paced sexual contacts, but failed

to affect morphine CPP [297].

6.2. Opiates and conditioned aversion paradigms

Morphine induced conditioned saccharin avoidance was

blocked by the DA D1 antagonist, SCH39166 and to a lesser

degree by the DA D2 receptor antagonist, raclopride [349].

Naloxone’s dose-dependent induction of conditioned place

aversion in rats given a single morphine exposure [1281] was

accompanied by c-Fos activation in the central, but not medial

nucleus of the amygdala [553]. Pairing DAMGO with saccharin

reduced intake of the saccharin cue to the same degree in both

Lewis rats and Fisher rats that are more sensitive to morphine

[710]. Bilateral excitotoxic lesions of the central nucleus of the

amygdala or BNST blocked conditioned aversion induced by

naloxone-precipitated withdrawal, but did not changes other

opiate withdrawal signs. Conditioned place aversions induced

by naloxone-precipitated morphine withdrawal were blocked

by NMDA (MK-801, PCP), AMPA (GYKI52466) and metabotropic

(AP-3, MCPG) antagonists, and reinstated by haloperidol [579].

Barium, a putative blocker of GIRK channels, potentiates the

conditioned aversion, but not the somatic signs of naltrexone

precipitated morphine withdrawal [1041]. The ability of

nicotine to attenuate naloxone-induced conditioned place

aversions was blocked an alpha7 nicotinic Ach receptor

subtype inhibitor, but not by an alpha4beta2 nicotinic Ach

receptor subtype inhibitor [826]. Central amygdala, but not

BNST lesions blocked morphine withdrawal-induced c-Fos

activation of the lateral and medial BNST [839].

Both buprenorphine and the CRF-1 antagonist, antalarmin,

blocked the acquisition of opiate withdrawal-induced condi-

tioned place aversions [1129]. The kappa agonist, salvinorin A

produced conditioned place aversion and decreased locomo-

tor behavior while reducing DA levels in the caudate-putamne,

but NAC in a NBNI-sensitive manner [1362]. Punishment-

suppressed remifentanil self-administration was reinstated

by lorazepam [910]. Pro-Enk KO mice, but not wild-type or

BEND KO mice failed to show a conditioned aversion to

naloxone, but all displayed both conditioned aversions to the

kappa agonist, U50488H and LiCl as well as morphine-induced

CPP [1096]. Clonidine, but not a selective alpha-2-adrenergic

receptor agonist, U14304, blocked conditioned place aversion

induced by naloxone-precipitated withdrawal. This blockade

also occurred with the alpha2 receptor and imidazoline 1

receptor agonist, rilmenidine, and was reversed by the alpha2

receptor antagonist, RX821002 [402]. The lowered hot-plate

latencies observed following a second exposure to the

stimulus was defined as an avoidance response which was

blocked by morphine or haloperidol treatment prior to the first

exposure [1134].

6.3. Opiates and drug discrimination and spatiallearning

Chronic, but not acute exposure to a 30% sucrose solution

significantly enhanced by three-fold the potency of nalbu-

phine to produce discriminative effects in rats [551]. Morphine

decreased the accuracy of temporal discrimination and

color matching by decreasing overall stimulus control, rather

than selectively affecting timing in pigeons [1267]. Pigeons

trained to discriminate either heroin or buprenorphine

from saline showed that nalbuphine generalized to both

groups. After discontinuation of L-alpha-acetylmethadol

treatment, the abilities of nalbuphine to induce heroin-key

or buprenorphine-key responding were markedly decreased

[389]. Heroin-induced discriminative stimulus effects could be

substituted in naltrexone-sensitive fashion to a strong degree

by morphine, weakly by muscimol, but not by any other GABA

ligand [1109]. Discriminative stimulus effects of acute

morphine followed by naltrexone in the squirrel were

increased in potency order by the following opioid agonists:

etorphine, fentanyl, levorphanol, heroin, methadone, nalbu-

phine and morphine [1279]. The increase in escape latencies

in spatial learning observed in diabetic micewas significantly

reduced by the delta-1 antagonist, 7-benzylidenenaltrexone,

but not by general delta or delta-2 antagonists; the delta-1

agonist, DPDPE increased spatial learning escape latencies in

both diabetic and non-diabetic mice [568]. Young mice display

better performance on a 3-day water maze protocol than older

mice, and display increased DYN levels in frontal cortex, but

not hippocampus. Aged pre-DYN KO mice display less

impairment in this paradigm than older wild-type mice;

no genotype difference was observed in younger mice

[855]. The kappa opioids, DIPPA, U50488H and ICI199441

substituted fully for the stimulus effects produced by spirado-

line [1178]. Rats with aluminum-induced learning and

memory impairments displayed facilitated spatial learning

and memory and enhanced hippocampal CA1 LTP following

naloxone [1074]. Heroin-dependent females displayed greater

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3419

spatial performance deficits than heroin-dependent males

with both groups performing worse than healthy volunteers

[713].

6.4. Opiates and memory

Pre-training morphine-induced impairments of passive

avaoidance was blocked by NMDA and enhanced by the

NMDA antagonist, AP-5. Co-administration of NMDA and

morphine on the test day enhanced morphine-induced

memory improvements, indicating state-dependent effects

[540]. Morphine administered before passive avoidance train-

ing produced memory impairments that were reversed by pre-

test morphine. Co-administration of H1 and H3 antagonists

respectively prevented and enhanced the pre-test morphine

effect, whereas H2 antagonism was without effect [1347]. Pre-

testing with nanogram level doses of morphine and naloxone

respectively prevented and enhanced morphine-induced

memory recall of a passive avoidance task [1170]. Facilitation

of a passive avoidance task by urocortin was insensitive to

naloxone [1173]. Pre-test morphine paired with milligram

doses of a COX-2 inhibitor prevented the former’s memory

impairment, whereas test day morphine paired with nano-

gram doses of a COX-2 inhibitor blocked the former’s memory

improvement [590]. Post-training administration of morphine

into the VTA blocked memory retention in a passive avoidance

task, an effect blocked by prior morphine sensitization.

Naloxone, D1 and D2 DA antagonists blocked this morphine

sensitization [1345]. Morphine shifted delay-discount func-

tions to the left resulting in decreased choices of a larger

reinforcer, whereas methylphenidate produced rightward

shifts resulting in increased choices of a larger reinforcer

[939]. Both heroin and the delta agonist, SNC80 dose-

dependently reduced schedule-controlled responding in

monkeys with drug combination producing an additive effect.

SNC 80 enhanced heroin-induced thermal analgesia, but did

not change the rate of heroin self-administration [1126]. The

abilities of (+)- and (�)-pentazocine to reverse scopolamine-

induced impairments of alternation performance were

impeded by the sigma antagonist, NE-100, but not by the

KOR antagonist, NBNI [498].

Pre-natal administration of morphine into chick eggs on

embryonic days 12–16 impaired long-term, but not inter-

mediate-term memory on a passive avoidance task 1 day after

hatching [191]. Whereas peripheral opioid antagonism facili-

tated male song production in European starlings, Menk

density in the VTA and MPOA correlated positively with male

song production [998]. Patients receiving immediate-release

morphine for palliative care showed reductions in pain, but

displayed impairments in anterograde and retrograde mem-

ory measures as well as performance on complex tracking

tasks. In contrast, performance on simple tracking tasks

improved [567].

7. Eating and drinking

This section will review ingestive effects as functions of opioid

agonists (Section 7.1), opioid antagonists (Section 7.2), and the

interaction of POMC-derived peptides (Section 7.3).

7.1. Opioid agonists and ingestive behavior

DAMGO-induced feeding elicited from the NAC was blocked by

VTA pretreatment with general, mu and kappa, but not delta

antagonists, whereas DAMGO-induced feeding elicited from

the VTA was blocked by NAC pretreatment with general, mu

and delta, but not kappa antagonists [112]. DAMGO increased

hedonic ‘liking’ reactions to sucrose in the posterior ventral

GP, but suppressed these reactions in the anterior and central

ventral GP. DAMGO stimulated feeding in the posterior and

central, but not anterior ventral GP. In contrast, bicuculline

induced eating, but did not change ‘liking’ reactions in any of

the three parts of the ventral GP [1102]. Morphine-induced

feeding displays peak effects during the middle of the light

phase of the light:dark cycle with DA deafferentation of the

ventral striatum shifting morphine’s peak orexigenic response

toward the dark phase [61]. Binge eating of palatable foods

induced by caloric restriction and footshock stress is more

sensitive to the orexigenic effects of butorphanol and the

anorectic effects of naloxone [114]. The regulation by the

striatal Enk system upon the hedonic impact of preferred

foods is reduced by muscarinic antagonism, an effect

modulated by hypothalamic–midline thalamic–striatal con-

nections involving the paraventricular thalamic nucleus and

orexin-coding hypothalamic energy-sensing and behavioral-

state-regulating neurons [582]. Scopolamine administered

into the ventral or dorsal striatum decreased food, but not

water intake over 24 h, and reduced pro-Enk, but not pro-Dyn

mRNA expression [951]. Morphine was as effective as LiCl in

suppressing schedule-induced polydipsia only when animals

were subjected to a massed feeding design relative to ad

libitum-induced feeding [835]. Central OFQ/N significantly

increased food intake and pecking frequency, but not

stepping, wing flapping or preening in male broiler-type

chickens [1].

7.2. Opioid antagonists and ingestive behavior

MOR KO mice were resistant to obesity and impaired glucose

tolerance despite having similar energy intake to wild-type

mice; this resistance was associated with a strong induction of

the expression of key mitochondrial enzymes involved in fatty

acid oxidation [1143]. NPY-induced feeding was reduced by

central pretreatment with general, mu, delta and kappa

receptor antagonists as well as by AS probes directed against

exons 1–3 of the MOR gene, exons 1 and 2 of the DOR gene,

exons 1–3 of the KOR gene, and exon 3 of the NOR gene [535].

NPY-induced feeding in the broiler chick was significantly

reduced by cotreatment with mu and mu-1, but not delta or

kappa opioid antagonists [294]. Whereas general, mu, mu-1

and delta antagonists decreased deprivation-induced intake

in meat-type chicks, mu, but not mu-1 antagonists decreased

DAMGO- and DADL-induced feeding, whereas the delta

antagonist, ICI174864 decreased DPDPE-induced feeding in

this species [140]. Naltrexone blocked the ability of diazepam

to enhance positive hedonic ‘liking’ reactions on the taste-

reactivity test of a bittersweet quinine-sucrose orally infused

solution, and disrupted diazepam-induced reductions of

aversive ‘disliking’ taste reactions [993]. Naloxone increased

suppression of sucrose intake in animals shifted from a higher

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83420

(e.g., 32%) to a lower (e.g., 6%) solution; animals slower in

recovery from contrast were more sensitive to naloxone than

rapidly recovering animals [925].

7.3. POMC-derived peptides and ingestion

Fasting, but not lipopolysaccharide-induced anorexia

increases POMC, NPY and CART expression in the arcuate

nucleus [401]. Food restriction immediately decreased Lenk

levels in the lateral septal area that gradually was reduced

further after 4 weeks of restriction [628]. Food restriction

lowers basal NAC pro-DYN levels relative to ad libitum-fed rats

with restriction-induced levels increased further by the D-1

receptor agonist, SKF-82958. NAC, but not striatal pro-Enk

is also increased in both feeding groups [460]. Cpe (fat/fat)

mice lacking in carboxypeptidase E displayed elevations

in hypothalamic pro-Enk and pro-TRH following food

deprivation, but not following exercise [190]. Melanin-con-

centrating hormone administered into the NAC shell pro-

duced feeding and a depressant-line action on the forced swim

test, whereas a selective antagonist produced opposite effects,

presumably by acting on Enk- and DYN-positive medium

spiny neurons in the NAC shell [403]. Withdrawal from

combined high-energy and ensure diets that promoted weight

gain decreased DYN gene expression in the arcuate and

ventromedial hypothalamic nuclei [36]. Anorexic and bulimic

patients displayed opposite significant correlations between

their total eating disorder inventory-2 score and autoantibo-

dies against AMSH [352]. The serotonergic and noradrenergic

reuptake inhibitor decreased plasma BEND as well as leptin,

insulin and NPY levels in obese women who displayed weight

loss [60].

8. Alcohol and drugs of abuse

The interaction between opiates and other drugs of abuse

continues to be a vigorous area of investigation, and this

section is organized into examination of opioid action in the

general area of drugs of abuse (Section 8.1), in opiate self-

administration (Section 8.2) and in interactions with ethanol

(Section 8.3), THC (Section 8.4), stimulants (Section 8.5) and

other abused drug classes (Section 8.6).

8.1. Opiates and drugs of abuse: reviews

A review [634] examines the molecular genetics and pharma-

cogenetics of opiate and cocaine addictions, focusing primar-

ily on genes of the opioid and monoaminergic systems

associated with or evidently linked to opiate or cocaine

addiction. Another review [317] summarizes clinical pharma-

cokinetic evidence of buprenorphine in the treatment of

opioid dependence. A third review [705] examines PET imagery

of the occupancy of opiate receptors by substitute drugs in

opiate addicts. The evidence for neuronal release of endo-

genous opioid peptides by inhalation of general anesthetic

drugs is also reviewed [960]. A fourth review [225] presents a

treatment algorithm for dose and route of naloxone admin-

istration for acute opioid intoxication. A perspective [222]

indicates that the prevelance of abuse was oxycontin-

hydrocodone> other oxycodone > methadone > morphine >

hydromorphone > fentanyl > buprenorphine.

8.2. Opiates and self-administration studies

8.2.1. Animal studiesThe increased consumption of morphine in drinking water by

C57BL/6J mice relative to DBA/2J appears to be due to genes on

chromosome 10 proximal to D10Mit124 using reciprocal

congenic strains [351]. Morphine self-administration

increased the labeling of the AMPA GluR1 receptor subunit

on the plasma membrane of dendrites in the baso-lateral

amygdala [410]. Morphine self-administration in rats was

decreased by pre-session, but not post-session treatment with

the monoamine oxidase inhibitor, selegiline without affecting

cue-induced reinstatement; selegiline attenuated ptosis, but

not other withdrawal signs during naloxone-precipitated

withdrawal [436]. Morphine self-administration was also

reduced by systemic ascorbic acid administration that also

reduced subsequent naloxone-precipitated withdrawal signs

[13]. Acquisition, but not maintenance of heroin self-admin-

istration in rats is blocked by venlafaxine, a serotonin/

norepinephrine reuptake inhibitor [743]. Heroin self-admin-

istration behavior maintained on a PR, but not continuous

reinforcement schedule was enhanced by THC and the CB1

agonist, WIN155212-2, but not by an inhibitor of anandamide

transport or and inhibitor of fatty acid amide hydrolase [1112].

AS directed against an activator of G-protein signaling 3 into

the core, but not shell of the NAC eliminated reinstatement of

heroin seeking behavior in dependent self-administering rats

[1319].

Cue-induced reinstatement of heroin seeking behavior is

blocked by the mGluR2/3 agonist, LY379268 [121], but

potentiated by infusion of a GABA agonist mixture into the

prelimbic area that is activated by heroin cues [1047]. Cue-

induced reinstatement of heroin seeking enhanced c-Fos

expression in the medial part of the lateral habenula nucleus

[1356]. Chronic heroin decreased [35S]GTPgammaS binding

stimulated by DAMGO and a heroin metabolite in medial

thalamus and amygdala, but not cingulate gyrus or NAC

without changing MOR binding [746]. Reinstatement of opiate

drug-seeking behaviors is triggered by chemical activation of

lateral hypothalamic orexin neurons [474]. Response rates of

heroin seeking induced by contextual stimuli is similar to rates

during heroin self-administration training with these rates

enhanced to a greater degree by discrete conditioned stimuli

and also discriminative stimuli [1376]. Reduced heroin and

cocaine seeking during extinction and drug-induced reinstate-

ment are observed in rats maintained on chronic buprenor-

phine [1117]. Whereas heroin increased M6G synthesis and

decreased M3G synthesis, naltrexone with or without heroin

increased M3G synthesis [33]. Using PET scan analyses, acute

methadone treatment to rats dose-dependently increased the

bio-distribution of [(11)C]-diprenorphine, but no change in

binding. However, opioid-dependent human subjects failed to

display changes in either measure [795]. Chronic selegiline

decreased responding during extinction of morphine self-

administration, but failed to modify these measures during

reinstatement or reacquisition of morphine self-administra-

tion [437]. Both contingent and non-contingent heroin

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3421

administration produced qualitatively similar gene expression

profile in the NAC core, indicating its putative role in the

mediation of the persistent pharmacological as opposed to

cognitive effects of addictive drugs [538]. Heroin treatment

increased c-Fos activation of a number of circumventricular

organs including the vascular organ of the terminal laminar

and sub-fornical organ as well as the NTS [285]. The breakpoint

for self-administration of a speedball cocaine–heroin mixture

on a PR schedule was significantly and dose-dependently

reduced by NAC pretreatment with mu (CTOP), D-1 (SCH23390)

or D-2 (raclopride), but not delta (NTI) antagonists [236].

Repeated buprenorphine decreased DOR affinity and up-

regulated KOR density with the latter effect nullified by

clorazepate [959].

8.2.2. Human studiesA repeat polymorphism in the pro-DYN gene had a weak

association in African-American relative to European popula-

tions in an opioid dependent relative to a control group [977].

Punishment induced risky decision-making on the Cambridge

risk task in methadone-maintained opiate users relative to

heroin users or healthy volunteers [327]. Nondependent opiate

addicts administered morphine display reductions in Stage 3,

Stage 4 and rapid-eye movement sleep, and increases in Stage

2 sleep [1068].

Post-mortem analysis of heroin addicts revealed an

increase in the activity of soluble puromycin-sensitive

aminopeptidase, but not other peptidases in the prefrontal

cortex relative to control brains [661]; positive opioid fibers

were more abundant in the basal ganglia, and coagulative

changes and edema were observed in the neuronal Nissl

bodies [685]. The rate of pretreatment overdose in Australian

heroin addicts failed to differ as a function of whether they

were prison drug service clients, residential rehabilitation

clients, residential detoxification clients or community drug

treatment clients [849]. Definitions about the causes of opioid-

related deaths in Australia revealed a two-fold difference in

the absolute number of accidental deaths reported between

Australian states [546]. However, there was a reduction in

overdoses among those clients that entered maintenance

therapies and residential rehabilitation relative to those who

were only detoxified or received no treatment [263]. Risk of

heroin overdose was associated with shifting from private to

public locations, co-use of benzodiazepines and alcohol, and

the self-reported amount of heroin used [289]. Risk of heroin

overdoses is greater in individuals with high levels of

incarceration; thus, prison or jail may be a primary interven-

tion site [868]. The rates of opioid poisoning deaths in New

Zealand were 5.94 (morphine), 1.34 (methadone) and 2.5

(dextropropoxyphane) per 100,000 prescriptions [981]. Enroll-

ment in the Australian treatment outcome study reduced

suicide attempts in female clients from 20% to 10%, but failed

to change the lower rate of suicide attempts in males (�8.5%)

[262]. Oxycodone-related deaths in Palm Beach County were

most often observed in cases of combined drug toxicity [1292].

Sustained release naltrexone implants prevented opioid

overdose, but was less effective in polydrug substance abusers

[519]. Intranasal naloxone provides an effective needleness

alternative for treatment of opioid overdoses in a pre-hospital

setting [68]. Inhalation of diacetylmorphine after volatilization

(‘‘chasing the dragon’’) is more suitable than intranasal and

oral routes in developing alternatives to injectable treatment

in opioid dependent patients [608], and is pharmacokinetically

superior to the use of a heating device [606]. The deuterized

form of diacetylmorphine appears to be a reliable marker for

illicit heroin use by addicts in a heroin-assisted treatment

program [607]. Heroin overdoses paired with alcohol con-

sumption results in greater doses of naloxone needed for

resuscitation [151]. Heroin shortages reduced use to a greater

degree in younger relative to older users [274]. Such a shortage

in 2001, caused by low profits, increased law enforcement

success and reduced supplies from the Golden Triangle [276],

decreased fatal and non-fatal heroin overdoses, and did not

increase overdose rate of other abused drugs, but decreased

needle use and property crime [275]. Data from take-home

naloxone to reduce heroin death still appears anecdotal, and

should be studied in a more rigorous manner [47].

General anesthesia is not an effective adjuvant to naltrex-

one for heroin detoxification and rapid opioid antagonist

induction [227]. Normalization of drug excretion to urine

creatinine concentration reduces the variability of drug

measurement attributable to urine dilution, route of drug

administration and type of drug in opiate-dependent patients

[1165]. Patients undergoing anesthesia-assisted rapid detox-

ification displayed milder withdrawal symptom severity

[1176]. Patients with positive toxicology screens after ortho-

pedic surgery use opioids for longer durations than those with

negative toxicology screens [775]. Transitioning opioid-depen-

dent pregnant women in the second trimester from immedi-

ate-release morphine to methadone or buprenorphine could

be conducted with comfort and safety [557]. The demo-

graphics of opioid-dependent subjects receiving office-based

buprenorphine treatment includes a younger, white, less

dependent, and less-infected with hepatitis sample [1135].

Slow-release morphine treatment produced significantly less

depression and anxiety scores as well as fewer physical

complaints than slow-release methadone treatment for opioid

maintenance therapy [312].

Methadone-stabilized, but heroin-dependent participants

displayed greater EEG peak amplitude increases, particularly

over the central midline region following fentanyl self-

administration relative to fentanyl passive administration;

both treatments were naloxone-reversible [441]. Risk of

relapse in health care professionals was increased in those

who used a major opioid, had a coexsting psychiatric illness or

a family history of a substance abuse disorder [298]. Predictors

of treatment success for heroin dependence appear to be

largely similar for LAAM, buprenorphine and methadone [770].

Heroin-assisted treatment does not appear to be dependent

upon clinical characteristics except for previous abstinence-

oriented treatment with medical heroin prescription most

effective for the latter group [106]. Intramuscular naloxone

was more rapid than intra-nasal naloxone in prehospital

treatment for suspected opioid overdose, and increased

respiration quicker [583]. Slow-release oral morphine was

effective in reducing heroin and cocaine craving as well as

additional consumption of cocaine, but not benzodiazepines

in supervised urinalysis [632]. Anesthesia and sedation were

more effective in producing rapid detoxification in older

Australian heroin patients than clonidine or buprenorphine

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83422

paired with other symptomatic medications [290]. Buprenor-

phine treatment reduced clinical opiate withdrawal and

craving scores to a greater degree than clonidine in patients

undergoing acute heroin detoxification [884] and when paired

with naloxone in the NIDA clinical trials network [704].

Buprenorphine–naloxone combinations reduced heroin-

induced break point values and subjective responses at doses

that inactivated 80–90% of mu receptors in heroin-dependent

volunteers [229]. Pharmacists displayed positive attitudes in

dispensing buprenorphine–naloxone to patients with opioid

dependence [965]. Naltrexone paired with the benzodiazepine,

prazepam increased the number of patients remaining opioid-

free and abstinent [1124].

Reductions in heroin supply in New South Wales decreased

both fatal and non-fatal heroin overdoses with larger effects in

younger groups, and no clear increase in non-fatal overdoses

of cocaine, methamphetamine or benzodiazepines [273]. The

likelihood that a drug user witnessing another’s overdose

would call for medical help was related to the respondents

never having an overdose themselves and that the overdose

occurred in a public place. Fear of the police was the major

reason for not reporting another’s overdose [1195]. Although

non-injecting heroin users were more likely to be employed

than injecting heroin users in the Australian treatment

outcome study, the two groups did not differ in heroin use,

dependence symptoms, polydrug use, criminality, health or

psychpathology over a 12-month period [261]. Among people

arrested, declines in heroin use among African-Americans

were observed for subjects born since 1955 relative to those

born between 1945 and 1955, whereas declines in heroin use

among Hispanics were observed for subjects born since 1970

relative to earlier periods. Sniffing replaced injection among

African-Americans and Hispanics, but injection remained

steady in white addicts [416]. Opioid-dependent patients may

be prescribed ineffective doses of buprenorphine or dangerous

combinations of buprenorphine and benzodiazepines by

untrained general practitioners in France [350]. The metabo-

lites, hydroxypapaverine and dihydroxypapaverine displayed

high sensitivity, specificity and negative predictive values as

markers to detect illicit heroin use in opioid-dependent

patients [917].

Heroin use can lead to intermittent or constant exotropia or

divergence of the visual axes, whereas withdrawal may result

in intermittent or constant esotropia or convergence of the

visual axes [359]. Detection of a psychoactive substance

including morphine in oral fluid such as at a roadside is

highly predictive for the detection of the corresponding drug

or its metabolite in serum [1192]. A combination of hydro-

codone and acetaminophen produced abuse liability-related

subjective effects in recreational drug users [1335]. A clinically

prescibed dose of oral tramadol has abuse liability effects in

recreational drug users [1334].

8.3. Opiates and ethanol

A review [812] reviews the opioid ethanol link in describing

increased alcohol intake following opioid agonists and

decreased ethanol intake following opioid antagonists in

animals and humans as well as changes in opioid systems in

animals with high and low ethanol preferences. Proceedings

of a symposium examining the role of the endogenous opioid

system on the neuropsychopharmacological effects of ethanol

are reviewed [1034]. A second review [1119] indicates that

circadian functions of BEND-containing neurons involved in

alcohol reinforcement become disturbed after chronic alcohol

intake.

8.3.1. Animal behavioral modelsA review [757] indicates that the ability of CB receptor

antagonists to block opioid peptide release facilitates reduced

ethanol consumption. Male KOR KO mice drank less alcohol

and saccharin, but had a higher preference for quinine.

Female KOR KO mice also showed less alcohol consumption,

although all female genotypes consumed more alcohol than

corresponding male groups [629]. MOR KO mice displayed

reductions in the anxiolytic and stimulant properties of

ethanol, and showed earlier affective and physical signs of

ethanol withdrawal than wild-type mice [406]. MOR KO mice

display significantly less ethanol-induced Fos in the lateral

septum, suprachiasmatic nucleus and lateral geniculate

nucleus, significantly greater ethanol-induced Fos in the

ventral pallidum and GP, but similar levels of ethanol-induced

Fos in the paraventricular thalamus, dorsal hypothalamus,

PVN, SON, LC, Edinger–Westphal and lateral PBN [618].

Preweanling rats exposed pre-natally to ethanol displayed

greater ethanol intake and more ingestive responses to the

taste of ethanol, effects blocked by simultaneous pre-natal

naloxone pretreatment [39]. The dipeptide, glycyl-glutamine

administered into the NAC shell reduced ethanol-induced

intake to the same degree as BEND (1–27) or naltrexone [984].

Ethanol-induced locomotor activity was reduced by general

and combined mu1/2, but not by mu1 or delta opioid

antagonists [916].

Naltrexone in the NAC blocked the rapid ethanol-induced

tolerance to motor incoordination [1222]. Naltrexone reversed

chronic ethanol-induced increases in VTA TH mRNA, whereas

naltrexone–ethanol combinations increased striatal DA [671].

Both baclofen and naloxone reduced alcohol-reinforced

responding in alcohol-preferring rats with the former delaying

the onset of the responses [738]. Ethanol induced CPP was

decreased by baclofen, a GABA-B agonist or methylnalox-

onium, a nonselective opioid antagonist when either was

administered into the VTA, but not the NAC [75]. Ethanol

decreased Morris water maze spatial performance in castrated

rats, an effect reversed by testosterone. Testosterone also

blocked the corresponding ethanol-induced increases in

cortical and hippocampal BEND levels [589]. A single NBNI

treatment produced long-lasting increases in ethanol intake,

particularly in those animals with greater baseline intake; it

fails to alter ethanol-induced CPP [807]. Acquisition and

expression of alcohol-induced drinking in Sardinian alco-

hol-preferring rats were blocked by a combination of

naltrexone and baclofen, but not by either drug alone [228].

Alcohol withdrawal increased pro-DYN mRNA and KOR

density in withdrawal seizure-prone relative to withdrawal

seizure-resistant mice [74]. The pattern of morphine admin-

istration rather than the dose or number of drug exposures is

the most important factor in morphine-induced locomotor

sensitization with ethanol exposure interfering with this

process in alcohol-preferring rats [873].

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3423

8.3.2. Ethanol-induced changes in opioid systemsWarsaw high-preferring alcohol rats receiving acamprosate

displayed a smaller increase in BEND following acute ethanol

treatment, whereas repeated acamprosate to Warsaw low

preferring alcohol rats prevented ethanol-induced BEND

increases [1342]. Chronic ethanol up-regulated DOR expres-

sion in the hippocampal CA1 region, but down-regulated MOR

expression in the hippocampus, cortex, striatum, colliculi and

NAC [1028]. Whereas acute ethanol enhanced the ability of

CRF and VIP to stimulate BEND release from medial basal

hypothalamic cell cultures, chronic ethanol reduced CRH and

VIP-induced responses [947]. Moderate, but not low or high

ethanol doses produced a prolonged elevation of Menk in the

NAC [766].

8.3.3. Human studiesHuman genotypes with the A118G single-nucleotide poly-

morphism in exon 1 of the MOR gene showed significantly

greater attributable risk (11.1%) for alcohol dependence in

Swedish subjects, an effect that did not distinguish between

type 1 and 2 alcoholism [65]. Familial low-risk non-alcoholic

participants had higher plasma BEND levels than low-risk

alcoholic subjects who were in turn higher than high-risk non-

alcoholic and alcoholic subjects [250]. Plasma BEND and ACTH

concentrations as well as areas under the curve were lower in

familial high risk than low risk alcoholics [407]. Alcohol

abstinence over 3–5 weeks increased MOR receptors in the

ventral striatum and NAC as measured by PET, and correlated

with reports of increased alcohol craving [487].

A meta-analysis of naltrexone treatment for alcohol

dependence revealed that earlier studies showed a larger

effect size than later studies, and that multi-center studies

showed generally smaller effects than single-site studies [345].

Positive predictors of naltrexone effectiveness in alcoholic

patients included family history of alcoholism, early age of

onset of drinking problems and comorbid use of other drugs of

abuse [1018], and naloxone appears to be more efficacious in

female alcoholics [592]. Naltrexone reduced the number of

drinks and reduced obsessive-compulsive drinking scores in

adolescent patients [270], and alcohol craving in dependent

Taiwanese subjects [515], but failed to add any benefit when

combined with serataline in late-life depressed alcohol-

dependent patients [889]. Combined naltrexone and cognitive

behavioral or motivational enhancement therapy proved most

effective in preventing relapse in alcohol-dependent patients

[32]. Although acamprosate was more effective than naltrex-

one in preventing alcohol relapse, it was used more frequently

in Indian patients with higher incomes and familial support

[72], and a rationale for combining these two drugs in treating

alcohol dependence is presented [774]. gamma-Hydroxybu-

tyric acid, used to induce alcohol abstinence produces craving

that is blocked by naltrexone [157]. An association of

increasing leptin concentrations with relapse to renewed

alcohol intake in detoxified alcoholics can be blocked by

combined treatment with naltrexone and acamprosate [591].

8.4. Opiates and THC

A review [1235] summarizes the cellular and molecular basis of

CB and opioid interactions.

8.4.1. Animal behavioral studiesCB1 receptor KO and wild-type mice display the same

modifications in analgesic, locomotor, anxiety and anti-

depressant responses following the dual inhibitor of Enk-

degrading enzymes, RB101 [544]. Non-selective and CB2

agonists decreased pain responses induced by carrageenan

to the same degree as a 3 mg/kg dose of morphine or rofecoxib

[319]. Priming injections of heroin or the CB-1 agonists,

WIN55212-2 or CP55940 completely restored heroin-seeking

behavior in heroin-abstinent rats with both the priming and

reinstatement effects blocked by pretreatment with naloxone

or the CB-1 antagonist, SR141716A [343]. Heroin, but not SNC-

80 or U50488H shifted the THC discrimination to the left,

whereas naltrexone, but not NTI or NBNI shifted both the THC

discrimination to the right and reversed heroin’s leftward shift

[1110]. THC enhanced heroin-induced locomotion and con-

comitantly increased heroin-induced c-Fos in the dorsomedial

striatum and core of the NAC while reducing heroin-induced

c-Fos in the BNST, PAG and central nucleus of the amygdala

[1092]. THC and morphine increased break points for food

reinforcement but only when food was delivered during

testing. The CB-1 antagonist, rimonabant and naloxone

decreased break points, and abolished the effects of both

agonists [1111].

8.4.2. Anatomical, molecular and neurochemical studies

CB1 KO mice displayed increases in KOR and DOR, but not MOR

activity in the C/P, but not in the NAC [1213]. Whereas

morphine, DAMGO and the CB-1 agonist, ACEA suppressed

capsaicin-induced pERK expression in the dorsal horn of intact

rats, only the CB-1 agonist continued to suppress this response

1 week after spinal nerve ligation and neuropathy develop-

ment [580]. Morphine-tolerant rats display reduced cannabi-

noid receptors in the hippocampus and cerebellum, and show

reductions in CP55940-stimulated [35S]GTPgammaS binding in

the limbic system. CP55940 exposure increased MOR in the

lateral thalamus and PAG and increased DAMGO-stimulated

[35S]GTPgammaS binding in the NAC [1236]. BEND-immunor-

eactive hypothalamic neurons displayed a rightward shift in

the inactivation curve for the I(A) and an increase in the half-

maximal voltage without changes in peak current magnitude

following CB-1 agonists, effects blocked by a CB-1 antagonist

[1159].

8.5. Opiates and stimulants

A review [953] examines the indirect role of kappa agonists as a

potential treatment of stimulant dependence. A second review

[1043] summarizes the genetic evidence linking addiction to

opioids and cocaine.

8.5.1. Animal behavioral studiesReinstatement of cocaine lever pressing was blocked by

ventral GP administration of CTAP, and enhanced by ventral

GP morphine in a CTAP-sensitive manner. Cocaine reinstate-

ment was associated with reduced extracellular GABA in the

ventral GP with this effect prevented by CTAP [1160]. Both

cocaine- and heroin-withdrawn rats displayed attentional

behavioral disturbances on a five-choice task during the early

withdrawal period, but heroin-withdrawn rats showed a

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83424

persistent reduction in motivation to collect food reward after

6 weeks of withdrawal [252]. Combinations of cocaine with

heroin, alfentanil or nalbuphine increased self-administration

both in terms of the total number of injections (income) and

total responses (labor); the addition of opioids made cocaine

consumption more resistant to increased rersponse costs

(inelasticity) [1014]. Cocaine alone, heroin alone or cocaine–

heroin combinations dose-dependently increased drug choice

and decreased food response rates in a choice paradigm in

monkeys [851]. Combined heroin–cocaine (speedball) did not

result in different break points on a PR schedule than cocaine

alone. Although cocaine was always preferred over heroin in a

choice paradigm, some speedball combinations were pre-

ferred over cocaine [1268]. Both steady-dose and escalating-

dose ‘‘binge’’ cocaine administration increased behavioral

stereotypy, intense head movements and increased pro-DYN

mRNA in the C/P, but not the NAC [1046]. Short-term (3 h)

withdrawal from ‘‘binge’’ cocaine administration increased

pro-DYN mRNA in the C/P, and increased MOR mRNA in the

frontal cortex [51]. Long-term (2 weeks) withdrawal from

‘‘binge’’ cocaine administration increased MOR binding in the

frontal and cingulate cortex as well as the C/P with no change

in adenosine receptor binding [50]. Naltrexone progressively

attenuates cocaine-induced reinstatement of extinguished

responding over consecutive reinstatement tests even as

discriminative lever-pressing during reinstatement is still

present [404]. MOR KO mice displayed reductions in cocaine

self-administration that was accompanied by increased

GABA-mediated frequencies of spontaneous IPSCs, but not

EPSCs onto DA neurons in the VTA [778]. However, MOR KO

mice and chronic naltrexone-treated mice displayed similar

acute cocaine-induced locomotor activity to controls and

displayed the same degree of cocaine-induced behavioral

sensitization [684]. KOR KO mice displayed an augmented

locomotor response to cocaine, but failed to display behavioral

sensitization following chronic cocaine while displaying

enhanced DA release in the NAC [192]. Chronic cocaine

blocked the anxiolytic action of the KOR agonist, U50488H

[639].

Meperidine analogues failed to produce changes in cocaine

locomotor effects or substituted for cocaine in drug discrimi-

nation, suggesting that their mu opioid effects contribute to

their poor in vivo efficacy [723]. Both the induction and

expression of methamphetamine-induced behavioral sensi-

tization were blocked by naltrexone [215]. Methamphetamine

and morphine co-administration increased lethality that was

blocked by NMDA receptor antagonism and immediate post-

injection cooling [841]. Methylenedioxymethamphetamine

produces a CPP that can be blocked by naloxone, the CB-1

antagonist, SR141716A, and the 5-HT-3 antagonist, tropisetron

[129].

8.5.2. Anatomical, molecular and neurochemical studiesMOR binding was increased in the anterior frontal and anterior

cingulate gyri of abstinent cocaine users from 1 day to 12

weeks after cocaine cessation; shorter-term effects were

observed in the lateral temporal cortex [429]. Morphine,

cocaine and methamphetamine markedly elevate BDNF

mRNA in the prefrontal cortex [673]. Cocaine administration

increased pro-DYN mRNA expression in the rostral and caudal

subregions of the striatum, but only produced this effect in the

caudal subregion the Flinders sensitive line of rats displaying

hypercholinergic responsivity [333]. Induction of deltaFosB in

the VTA occurs after chronic amphetamine and cocaine

treatment, but not following chronic opiates or stress [928].

Cocaine-induced increases of c-Fos and DYN were prevented

in stress-activated and MAPK-1 KO mice [130]. Repeated

cocaine exposure increased excitatory responding to mor-

phine and glutamate in ventral GP neurons, whereas the

effects of GABA were diminished [787]. Cocaine withdrawal

increased VP mRNA in the amygdala in a naloxone-sensitive

manner, but without changing MOR mRNA levels [1377]. The

serotonin neurotoxin, p-chloroamphetamine blocked cocaine-

induced and methamphetamine-induced pro-DYN mRNA

expression in the matrix, but not patch compartments of

the rostral and middle striatum [511].

Methamphetamine increased FasL protein expression in

striatal GABAergic neurons that express Enk [549]. Metham-

phetamine-induced apoptosis of Enk and NOS striatal neurons

is more pronounced in NPY KO mice [1182]. Methampheta-

mine, but not morphine activate purified astrocytes in

cortical/glia co-cultures and displays longer periods of

behavioral sensitization after withdrawal [844]. Methamphe-

tamine produced exaggerated c-Fos expression in the NAC,

striatum and septum of NOR KO mice; NOR KO mice displayed

reduced c-Fos expression following vehicle treatment [874].

Methylphenidate-induced increases in cortical Homer 1a and

zif 268 expression were also correlated with increases in

striatal DYN and SP expression [1318]. The ability of ginseno-

sides to attenuate methamphetamine-induced behavioral

side effects through activation of adenosine A2A receptors

corresponds to the ability of ginsenosides to reduce striatal

pro-Enk mRNA activity and immunoreactivity [1078].

8.5.3. Human studiesAn association between cocaine dependence and a variable

nucleotide tandem repeat polymorphism in the 50 promoter

region of the pro-DYN gene was established [249]. A positive

linear relationship was found between total melanin content

of hair and C(max) of codeine, cocaine and their metabolites

following high dosing [1044]. Crack cocaine users displayed

greater levels of impulsivity and risk-taking than heroin users

with the former difference persisting after controlling for age

and gender [119]. Male cocaine users failed to display any

additive interactions between cocaine and the mu-kappa

opioid agonist, nalbuphine across a series of subjective mood

measures, cardiovascular responses or plasma drug levels as

compared to the agents administered alone [796].

8.6. Opiates and other drug abuse classes

Environments associated with the rewarding effects of

nicotine increase CRB phosphorylation in normal, but not

MOR KO mice. Naloxone blocked the conditioned molecular

(CREB) and conditioned rewarding effects of nicotine [1245].

Obese smokers administered themselves nicotine through

cigarettes less than non-obese smokers, and showed lesser

hedonic effects. Mice placed on a high-fat diet failed to display

nicotine-induced CPP, and showed down-regulated MOR and

leptin receptors in the VTA [108]. Nicotine-dependent rats

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3425

undergoing withdrawal display elevated reward thresholds in

an intracranial self-stimulation paradigm as the sessions

increased. The same withdrawal-associated cues also ele-

vated reward thresholds in morphine-dependent rats as well

[585]. Naltrexone combined with nicotine replacement ther-

apy and psychosocial therapy produced greater cessation of

smoking in women [143]. Naltrexone, but not bupropion

reduced the relative reinforcing value of nicotine in a cigarette

smoking choice paradigm [1020]. Naltrexone decreased cigar-

ette consumption, expiratory carbon dioxide levels and

reduced smoking urges without changing plasma BEND or

DYN levels [672].

9. Sexual activity and hormones, pregnancy,development and endocrinology

This section will examine developments relating the endo-

genous opioid system to sexual activity (Section 9.1), preg-

nancy (Section 9.2), development (Section 9.3), and general

endocrinology (Section 9.4).

9.1. Sexual activity and hormones

A review [59] indicates that BEND has both excitatory and

inhibitory effects on sexual arousal. MOR labeling was found

on the head and tail of equine sperm, with motility and sperm

velocity differentially and biphasically affected by low and

high doses of naloxone [15]. Although female MOR KO mice did

not differ in either active or passive avoidance of the male, and

although estrogen and progesterone facilitated lordosis in the

MOR KO mice, these animals displayed deficits in lordosis

quotient score [1088]. Young male white New Zealand rabbits

displayed greater numbers of mounting and ejaculations than

older counterparts, but both groups showed enhanced sexual

activity following low naloxone doses [372].

Older senescence-accelerated female mice displayed

longer estrus cycles, lower serum estradiol, higher pituitary

LH and lower hypothalamic levels of BEND and SP than

senescence-resistant strains [1332]. Dehydroepiandrosterone

in ovariectomized female rats increased BEND levels in the

hippocampus, hypothalamus, anterior pituitary and in plasma

serum [88]. Central treatment with naloxone and melatonin

increased LH concentrations and the mean LH pulse ampli-

tude in ewes treated during the luteal phase of the estrus cycle

[806]. Morphine respectively increased and decreased LH

secretion from dispersed carp pituitary cells in males and

females; naltrexone abolished both opiate-mediated effects

[1107]. An upstream initiator-like element suppresses tran-

scription of the rat LH receptor gene in a manner distinct from

that of the upstream initiator-like suppressor element of the

rat DYN promoters [1330]. Naloxone and NBNI, but not NTI

blocked the suppression of LH pulses by CGRP [125]. GnRH

release from in vitro hypothalamic slices and from in vivo

MPOA were inhibited by OFQ/N; similar effects were observed

for plasma LH levels in a NOR antagonist-sensitive manner

[25]. GnRH neurons in the hypothalamic periventricular nuclei

projecting to MPOA were not immunoreactive for Enk in

female sheep brain [945]. Whereas GABA-B receptor stimula-

tion of the ventromedial hypothalamus activates GnRH/LH

release and decreases BEND tone, GABA-B blockade enhances

BEND concentrations with no effect of GnRH/LH levels [1193].

Prolactin increased BEND levels and the number of oocytes

ovulated in a naloxone-reversible manner [943]. Lactation

induced changes in Enk, DYN, NPY and TH in the ventromedial

and arcuate hypothalamic nuclei using a DNA microarray

analysis [1305]. Progesterone increased CSF DYN A concentra-

tions in ovariectomized ewes with ovariectomy decreasing

pre-pro-DYN mRNA in the pre-optic, anterior hypothalamic

and arcuate hypothalamic nuclei. Progesterone reinstated

these DYN mRNA levels in the first two, but not latter nucleus

[363]. Cortical allopregnanolone was maximally enhanced by

THC, significantly by morphine, but not affected by cocaine

[444]. DAMGO inhibited OXY release from neurohypophysial

terminals by blocking R-type Ca2+ channels [888]. Nalmefene, a

KOR agonist and MOR antagonist, elevated serum prolactin

levels in normal human volunteers [66]. OFQ/N-induced

increases in the prolactin secretory response does not involve

tuberoinfindibular, tuberohypophyseal or periventricular

hypophysial DA or serotonin activity [633]. The ability of

spinal estrogen to attenuate the exercise pressor reflex in cats

was more pronounced in intact as compared to ovariecto-

mized females; naloxone was more effective in rreversing

estrogen’s effect in intact relative to ovariectomized cats

[1049].

9.2. Pregnancy

Pregnant rats displayed increased pro-Enk A and MOR mRNA

expression in the NTS, but an inability to increase anterior

pituitary POMC mRNA expression following interleukin-1-beta;

the latter effect was reinstated by naloxone [138]. Oral

morphine in drinking water decreased antero-posterior length

and weight in embroyos, delayed neural tube development and

damaged the regulated neuro-ectoderm layer [847]. Chronic

morphine exposure during puberty decreased postpartum

prolactin secretion in adult female rats rearing their own or

fostered pups without changes in maternal behavior latencies

[145]. The ability of gluten exorphin B5 to stimulate prolactin

secretion was completely abolished by systemic pretreatment

with the peripherally acting opioid antagonist, naloxone

methobromide [336]. Naloxone restored the ACTH secretory

response to CCK that was attenuated in pregnant rats [305]. A

review [137] indicates that although BEND concentrations are

elevated in cows with disturbed milk ejection, naloxone could

not abolish this spontaneous response.

Pre-eclamptic women during labor had lower plasma BEND

levels than controls, and there was a negative correlation

between plasma BEND levels and both systolic and diastolic

blood pressure [313]. Whereas smoking reduced interleukin-1-

alpha concentrations in the colostrum relative to non-

smoking mothers, BEND and leptin levels were comparable

in both groups [1344]. Infants treated for neonatal abstinence

syndraome after birth had longer hospital stays that are

similar for an oral morphine preparation or methadone [653].

9.3. Development

MOR coupling to G i/o proteins increases during post-natal

development, increasing 19-fold between post-natal day 5 and

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83426

adult [1152]. The sexual dimorphism of testosterone metabo-

lism enzyme activity and catecholamine content in the pre-

optic area was reduced by pre-natal stress in a naloxone-

reversible manner [987]. Pre-natal morphine exposure

increased MOR density in the MPOA of intact males and

males treated with testosterone, but not in gonadectomized

males. Neonatal rats exhibited earlier up-regulation and faster

recovery of spinal pre-pro-DYN mRNA than adults during

CFA-induced peripheral inflammation [1359]. Pre-natal mor-

phine exposure respectively increased and decreased MOR

density in the VMH of ovariectomized females and of females

treated with estradiol benzoate [1099]. Maternal deprivation

for 3 h per day over the first 14 days sensitized these animals

as adults to morphine CPP and oral morphine self-adminis-

tration [1228]. Maternal separation altered hypothalamic DYN

B levels, medial prefrontal cortex levels of Menk-Arg6-Phe7,

and amygdala OFQ/N levels, effects attenuated by pup ethanol

intake [459]. Second-generation pups born to rats (first-

generation) whose mothers were exposed to morphine during

pregnancy showed slower righting responses, less weight and

shorter ano-genital distances than their first-generation

parents in the immediate post-natal period [1098]. Whereas

the ED50 of respiratory depression induced by fentanyl

increased with post-natal ages of 7-day, 14-day, and adult

rats, 14-day-old pups displayed tolerance to fentanyl-induced

respiratory depression than the other groups [651]. Neither

morphine nor naltrexone altered ultrasonic vocalization

responses to the active dam, whereas only high morphine

doses prevented potentiations induced by repeated isolations

to the passive dam [1062]. Both systemic and intranasal

naloxone stimulated maternal behaviors 4–6 days after

delivery [292]. Naloxone doses, capable of producing distress

behaviors, increased extracellular 5-HIAA and HVA levels in

the medio-rostral neostriatum/hyperstriatum ventrale of

chicks, an effect abolished by co-treatment with DAMGO

[56]. Naloxone treatment prior to foot shock delivered to

pregnant females blocked the stress-induced reductions in

phagocytosis in peritoneal macrophages of male and female

offspring 30 days after birth [361]. Naloxone increased the

thickness of the perichondral bone of the femur in chick

embryos [706]. Morphine produced similar effects as tincture

of opium administered in ethanol to newborns suffering from

neonatal abstinence, while avoiding some of the alcohol’s

unwanted side effects [658]. Neonatal treatment with the

neurosteroids, pregnenolone and dehydroepiandrosterone,

increase positive cells containing glial fibrillary acidic protein

and NPY, but not DYN A in the CA3 region of the hippocampus

of rats after puberty [1080].

9.4. Endocrinology

Growth hormone administered to hypophysectomized rats

normalized the expression of the 72 kDa, but not the 48 or

36 kDa proteins of the DOR in the cerebral cortex of rats [929].

Morphine induced a positive modulating effect on growth

hormone secretion in patients with active acromegaly [94].

Prostaglandin E2 release was evoked by spinal DYN A and DYN

A(2–17) through a spinal p38 MAPK mechanism of action

[1141]. Lipopolysaccharide, a bacterial endotoxin significantly

increases CRF immunoreactivity in the parvocellular PVN, and

eliminates the naloxone-induced increase in serum LH

concentrations in female rats; CRF itself blocks naloxone-

induced LH release as well [480]. Plasma VP increases in ferrets

by morphine is blunted by ondansetron [1288].

10. Mental illness and mood

This section summarizes opioid involvement in mental illness

(Section 10.1) and mood (Section 10.2).

10.1. Mental illness

A review [970] examines the effects of SSRI’s and opioid

antagonists on stereotypy displayed by humans, especially in

autism. Naltrexone treatment over a 6–10-week period pro-

duced 30% reductions of symptoms in subjects with deperso-

nalization disorder [1084]. Immobility following the forced

swimming test in mice which is an animal model of depression

was blocked by agmatine, fluoxetine and morphine; the anti-

depressant actions of agmatine were reversed by general, mu

and delta, but not kappa receptor antagonists [1383]. MOR

binding in the left insular cortex was less in bulimic subjects

than controls and correlated negatively with fasting behavior

[83]. Whereas naltrexone exacerbated depressive symptoms in

a patient co-morbid for alcohol abuse and depression, switch-

ing to buprenorphine decreaseddepression andalcohol craving

[1052]. Depressive behavior on the forced swim test in Flinders-

sensitive rats was significantly reduced by wheel running, an

effect accompanied by increased hippocampal cell prolifera-

tion. However, increases in DYN or BDNF correlated with wheel

running, but not anti-depressant activity [105]. The antide-

pressant actions of CPMPH Mannich base were blocked by

sertonergic, noradrenergic and dopaminergic, but not opioid

antagonism [1002]. The video-tracking use of reductions in

submissive behaviors in rats and mice indicated anti-depres-

sant activity induced by chronic imipramine, fluoxetine or

maprotiline, but not NTI [938]. Morphine administration once

per week reduced symptoms in some treatment-resistant

obsessive-compulsive disorder patients [623]. Both sustained-

release buproprion and naltrexone were equally effective in the

treatment of pathological gambling [258]. Naltrexone produces

clinical improvement of kleptomania symptoms in patients

treated for up to 3 years [435].

10.2. Mood

MOR binding indices did not differ between suicide victims

and controls in the prefrontal cortex or pre-post central gyri

although the K(D) was lower in the former site and higher in

the latter site [1343]. Patients with chronic fatigue syndrome

failed to display differences in plasma cortisol or in the ACTH

and cortisol responses to naloxone or ovine CRF [533].

11. Seizures and neurologic disorders

This section summarizes the research examining the role of

the endogenous opioid system in the mediation of seizures

(Section 11.1) and neurological disorders (Section 11.2).

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3427

11.1. Seizures

Fentanyl decreased the latency, but increased the severity of

lidocaine-induced seizures in a naloxone-reversible manner

[206]. The anticonvulsant actions of tramadol were blocked by

general and kappa, but not delta antagonism, and enhanced

by both diazepam in a flumazenil-reversal manner and

baclofen in a GABA-B receptor antagonist-sensitive manner

[756]. Agamtine enhanced the anticonvulsant actions of

morphine in synergistic fashion and blocked by the alpha-2-

adrenergic antagonist, yohimbine [988]. The eliptogenic-

sensitive NHE1 null mouse has a decline of DOR expression

in the hippocampus and cortex [1368]. Heroin seizures can be

detected by micellar electrokinetic chromatography [26].

Thymoquinone, a muscle relaxant and hypnotic blocked

pentylenetetrazole-induced seizures following central admin-

istration, an effect reversed by naloxone and flumazenil [513].

Slowing the rate of SNC-80 intravenous infusions minimized

delta agonist-induced convulsions without altering its anti-

depressant actions on the forced swim test [560]. Although low

and high doses of the delta agonist, SNC-80 reduced

pilocarpine-induced seizure severity, high SNC-80 doses

produced prolonged status epilepticus, indicating both anti-

and pro-convulsant actions [73]. Borna disease virus-infected

rats displayed seizures and dyskinesias following naltrexone

and the CB1 antagonist, SR141716A [1108].

11.2. Neurological disorders

Deer mice displaying high levels of stereotypic jumping

behaviors possess lower Lenk and higher Dyn/Enk content

ratios in the striatum relative to animals with low levels of

stereotypic jumping [952]. Rats with 6-OHDA lesions display

behavioral sensitization following subchronic intermittent L-

DOPA that produces increased zif 268 mRNA labeling in

DYN(+) striatonigral cells and a down-regulation of DYN(�)

striatopallidal and striatonigral cells [167]. In a rat model of L-

DOPA-indued dyskinesia, regulated cytoskeletal (Arc)-asso-

ciated protein is up-regulated as well as FosB, Nur77 and

Homer 1a, which expresses pro-DYN mRNA [1060]. Denerva-

tion by 6-OHDA induced neurotensin and Nur77 mRNA

expression in Enk striatal neurons, whereas L-DOPA treamt-

ment produced further neurotensin expression limited to DYN

cells in the lateral striatum. Both effects were blocked by

SCH23390, a D1 receptor antagonist [1128]. Striatal 6-OHDA-

induced DA depletion increased apoptogenic proteins as

caspase-3 and fractin in Enk striatopallidal, but not SP-

striatonigral neurons [38]. Bilateral 6-OHDA treatment in the

dorsolateral striatum produced akinesia and decreased pro-

Enk A mRNA expression in the nondepleted striatal region; the

mGluR5 antagonist, MPEP alleviated the akinesia without

changing the peptide level [896]. The 5-HT-1A receptor agonist,

8-OH-DPAT coadministered with L-DOPA inhibited the latter’s

induced rotational behavior in unilaterally treated 6-OHDA

rats and prevented the increases in DYN and glutamate mRNA

in the denervated striatum [1194]. Rats with unilateral DA

depletion by 6-OHDA lesions display abnormal DYN A

metabolites 1–18, 1–16, 5–17, 10–17, 710 and 8–10 in the DA-

depleted striatum [605]. U50488H potentiated 6-OHDA-

induced decreases in TH immunoreactivity and increased

pro-Enk mRNA in the striatum [765]. Whereas an adenosine

A2A receptor antagonist ameliorated the decrease in SN TH in

6-OHDA-treated animals, it failed to alter increased pro-ENK

mRNA expression in the dorsal striatum [124]. Animals with 6-

OHDA lesions in the SN enhance OFQ/N expression, and either

pharmacological antagonism or KO of the OFQ/N/NOR system

alleviates Parkinsonian-like signs; this effect was associated

with decreased SN glutamate release [771]. Treatment with

3,4-methylenedioxymethamphetamine produces naloxone-

reversible ipsilateral rotations in animals with 6-OHDA lesions

in the medial forebrain bundle, and naloxone-insensitive

hyperactivity in normal animals [665].

Methamphetamine-induced decreases in striatal DA and

monoaminevesisular transporter binding were blocked by

both estradiol benzoate and the estrogen receptor modulator,

tamoxifen. In contrast, the methamphetamine-induced

increases in striatal pro-Enk mRNA levels were only blocked

by estradiol [264]. MPTP-lesioned dyskinetic squirrel monkeys

treated with L-DOPA displayed enhancements in MOR-

mediated G-protein activation in basal ganglia and cortex;

DOR and KOR-induced increases were more modest [200]. Pre-

pairing of placebo or naltrexone with dopaminergic agents in

MPTP Parkinsonian monkeys results in subsequent dyskinetic

behaviors induced by placebo or naltrexone alone [1032].

Morphine-induced enhancements of NAC DA efflux were

blocked by systemic administration of 5-HT-3 antagonists and

5-HT-1A agonists as well as by NAC 5-HT-3 antagonism [272].

Naltrexone decreases the anti-parkinsonian effects of L-DOPA

after 2 weeks and increases long-term dyskinesias in drug-

naı̈ve Parkinsonian monkeys treated with MPTP [1031]. DYN

A-induced ischemic spinal cord injury is blocked by inhibition

of glutamate carboxypeptidase II [724]. The tremors, but not

chewing movements induced by the anti-acetylacholinester-

ase, diisopropylfluorophosphate, are subject to delayed

tolerance development in MOR KO mice that are accompanied

by decreases in M2, but not M1 Ach receptor binding in the

striatum, but not cortex or hippocampus [1186].

Morphine respectively down-regulates and up-regulates

BACE-1 and BACE-2 mRNA in a naloxone-reversible, L-NAME-

reversible and SNAP-potentiating manner in beta-amyloid

metabolism [902]. Fluid percussion brain injury elevates CSF

OFQ/N that operates through an ERK and JNK, but not a MAPK

signaling pathway to impair cerebrovasodilation to prostaglan-

dins [1009]. Narcolepsy potently decreased orexin-containing

hypothalamic neurons expressing pro-DYN mRNA and neuro-

nal-activity-regulated pentraxin in autopsied brains [244].

12. Electrical-related activity,neurophysiology and transmitter release

The following section will review neurophysiological effects

described over the past year for mu (Section 12.1), delta and

kappa (Section 12.2) as well as ORL-1 (Section 12.3) agonists

and their receptors.

12.1. mu Agonists and receptors

Morphine as well as methamphetamine and nicotine stimu-

lated ascorbic acid release in the striatum, effects blocked by

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83428

frontal decortication or noncompetitive NMDA receptor

antagonism [450]. Systemic morphine suppressed both

short-latency and long-latency cellular responses to noxious

laser-heat stimuli evoked from the anterior cingulate cortex,

but only the long-latency component in the primary soma-

tosensory cortex of rats [644]. Anterior cingulate extracellular

glutamate is decreased by acute and chronic morphine as well

in a naloxone-sensitive manner [473]. Chronic morphine

withdrawal increased spontaneous activity, lowered signal-

to-noise ratios and produced weaker orientation and direction

selectivity in visual cortical cells that were significantly

improved by morphine re-exposure [481]. Subcortical soma-

tosensory evoked potentials elicited by electrical stimulation

of the forepaw elicited three peaks in cerebral cortex with the

third, but not other two components reduced by dorsal

column transaction. Systemic and intra-thalamic morphine

eliminated the remaining portion of the third component in a

naloxone-reversible manner [4]. Mechanically evoked noci-

ceptive responses of VPL thalamic neurons were larger in rats

exposed to carrageenan-induced inflammation than control

rats, and systemic morphine inhibited VPL responses in

inflamed, but not control groups [3]. Pre-natal morphine

potentiates lateral perforant path LTP from hippocampal

slices in female rats that is inhibited by the glucocorticoid

receptor antagonist, mifepristone (Ru486) [1229]. Hippocampal

glutamate is decreased by either acute or chronic morphine,

whereas naloxone-induced withdrawal increased hippocam-

pal glutamate [457]. Pre, but not post conditioning with

morphine produced neuroprotection against the deleterious

effects of hypoxia and hypoglycemia upon hippocampal

population spike amplitude in mice [24].

Morphine-induced increases in NAC DOPAC are attenuated

by ascorbate [966]. Chronic morphine over 3 weeks signifi-

cantly suppressed nicotine’s effects upon the frequency of

spontaneous IPSCs in NAC GABA medium spiny neurons, and

correspondingly enhanced the effects of mecamylamine and

tetrodotoxin upon the same population of cells [283]. A single

dose of morphine enhanced glutamate-induced, NMDA-

induced and AMPA-induced GABA release from the NAC core

3 weeks, but not 3 days after treatment [539]. Morphine-

induced increases in NAC and striatal DA were reduced by

either VTA or SN pretreatment with the muscarinic choliner-

gic antagonist, scopolamine [802]. Increased NAC DA release

by DAMGO consisted of a rapid onset followed by a slower

gradual component with mu antagonism reducing the second

component, delta-1 antagonism reducing the first component

and abolishing the second component and delta-2 antagonism

reducing the first component. delta-1 Agonist-induced

increases in NAC DA were blocked by delta-1 and to a lesser

degree by delta-2 and mu antagonism, whereas delta-2

agonist-induced increases in NAC DA were blocked only by

delta-2 antagonism [500]. U69593 inhibited EPSC amplitude in

principal, secondary and tertiary VTA neurons, whereas

DAMGO inhibited glutamate release in principal, secondary

and tertiary VTA neurons; the two agonist’s effects in tertiary

neurons correlated with one another [764]. MOR KO mice

exhibited a higher proportion of regular-spiking cells in

midbrain DA neurons that lacked any bursting activity [779].

Glutamate-evoked EPSCs in the amygdala were inhibited by

Menk and DAMGO, but not by DPDPE or U50488H in a CTAP-

sensitive manner [1379]. DAMGO reduced the frequency, but

not the amplitude or delay constant of miniature IPSC’s, but

not miniature EPSC’s, and also reduced the peak amplitude of

evoked IPSC’s, but not EPSC’s in central amygdala neurons

that project to the ventrolateral PAG; MOR was co-localized

with synaptophysin, a pre-synaptic marker in these neurons

[358]. PAG and LC brain slices treated with morphine or

fentanyl displayed enhancements in the frequency, but not

amplitude of presynaptic inhibition of evoked miniature IPSC

in beta-arrestin-2 KO mice [127]. Morphine produced short-

term desensitization of LC neurons that was slower and

smaller than Menk; Menk saturation prevented morphine-

induced desensitization [255]. In contrast, naloxone was

ineffective in blocking the inhibition of LC neurons by the

alpha-2-adrenergic-sensitive actions of citalopram [434]. The

decreased firing rates and synchronous oscillatory discharges

of LC neurons following morphine were reversed by kynurenic

acid, AP5 and CNQX [1378]. Serotonin efflux from the DRN was

disinhibited by DAMGO acting with AP5 and DNQX, and

inhibited by U50488H [1164]. Endomorphin-1 reduced the

frequency and amplitude of spontaneous EPSC’s, the fre-

quency, but not amplitude of miniature EPSC’s and the

frequency of spontaneous IPSC’s in the NTS following

stimulation, effects sensitive to general and mu receptor

antagonism [411]. Naloxone greatly inhibits catecholamine

release evoked by muscarinic and nicotinic receptor stimula-

tion as well as by membrane depolarization in the isolated rat

adrenal gland [595].

Morphine suppressed noxious and nonnoxious responses

of spinal wide dynamic range neurons in the dorsal horn to a

greater degree rostral relative to caudal to a spinal cord injury

[1258]. The ability of dipyrone to inhibit dorsal spinal wide

dynamic range neurons to mechanical noxious stimulation of

the hindpaw was blocked by naloxone treatment in the

ventrolateral or lateral PAG, NRM or locally onto the spinal

cord [1227]. Local application of morphine suppresses gluta-

mate-evoked activities of C and Adelta afferent fibers in rat

hairy skin [1185]. Morphine and DPDPE inhibited slow ventral

root potentials in a naloxone-sensitive manner, and inhibited

body movement induced by formalin or capsaicin in neonatal

rats [892]. NK1 receptor internalization evoked by either dorsal

root C-fiber stimulation in vitro or by hindpaw compression in

vivo was reduced by mu (DAMGO, morphine), delta (DPDPE),

but not kappa agonists [619]. DAMGO inhibited evoked EPSCs

of rat SG neurons, an effect blocked by adenosine A-1 receptor

antagonists, and biphasically affected by A-2 receptor antago-

nists [6]. Both a tramadol metabolite and DAMGO produced

similar CTAP-sensitive and yohimbine-insensitive outward

currents in adult rat substantia gelatinosa neurons [614].

Spared nerve injury and spinal nerve ligation decrease

DAMGO-induced inhibition on presynaptic primary afferent-

evoked EPSC’s and miniature EPSC’s in dorsal horn neurons,

and decrease DAMGO-induced post-synaptic K+ channel

opening action on lamina II neurons and inhibition on ERK

activation, but only in those spinal segments affected by the

injuries. This specificity is accompanied by decreased MOR

expression [616]. Ca2+ currents in DRG neurons are inhibited

by DAMGO, DADL and U50488H, but not by DPDPE or Delt II;

DADL-induced inhibition is reversed by CTAP pretreatment

[1249]. Naloxone blocked remifentanil-induced potentiations

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3429

of NMDA-induced inward currents in lamina II of the spinal

cord [456]. Whereas morphine and endomorphin-2 decreased

the firing frequency of the isolated spinal polysynaptic reflex

in a naloxonazine-sensitive manner, endomorphin-1 reduced

the mean amplitude of this response in a naloxonazine-

sensitive manner [1163]. Endomorphin-1 produced a short

phase of potentiation followed by a long-lasting inhibition of

both fast and slow responses of nodose sensory neurons to

ATP that interacted with purinergic receptors and were

differentially sensitive to intracellular GDP and pertussis

toxin [216]. Endomorphin-1 was more potent than endomor-

phin-2 in inhibiting synaptic transmission in the spinal cord

dorsal horn [682]. Trigeminal C-fiber nociceptors activated by a

low current but long pulse of an infrared diode laser were

sensitized by capsaicin, but inhibited by morphine [1208]. The

morphine-induced Straub-tail assay was used to determine

that silperisone was most effective as a muscle relaxant [342].

The reduction in C-fiber responses in the transected spinal

cord by the volatile anesthetic, sevoflurane was reversed by

naloxone and bicuculline [1266]. Naloxone reversed the ability

of halothane to inhibit nociceptive spinal withdrawal reflexes

but not spinal dorsal horn wide-dynamic range neuron

activities in spinalized rats [1329].

12.2. delta and kappa Agonists and receptors

DOR stimulation produced presynaptic inhibition of GABAer-

gic synaptic currents in the PAG only following repeated

morphine treatment and prolonged MOR stimulation and

expression of beta-arrestin-2 [463]. The two enantiomers of

the non-peptide DOR agonist, TAN-67 increased NAC extra-

cellular DA levels in a naloxone-insensitive, tetrodotoxin-

insensitive and Ca2+-insensitive manner; these effects were

prevented by alpha-methylparatyrosine, reserpine, NMDA

antagonism, and by free radical scavengers [382]. More SP-

sensitive PAG neurons than SP-insensitive PAG neurons

produced Menk-induced outward currents, an effect blocked

by SP administration [307]. NTI prevented the ability of high-

frequency, but not low-frequency transcutaneous electrical

nerve stimulation to release aspartate and glutamate from the

dorsal horn [1101].

The kappa agonist, U69593 attenuated the ON-cell burst in

RVM neurons in a kappa antagonist-sensitive manner, and

decreased activity in some OFF-cells without changing tail-

flick latencies. RVM U69593 blocked morphine analgesia and

suppressed the latter’s excitation of RVM OFF cells [798].

12.3. ORL-1 agonists and receptors

NOR KO mice displayed abberent hippocampal place cell

activity in that they were less stable, had noisier positional

firing patterns, larger firing fields and higher discharge rates.

These animals displayed enhanced hippocampal LTP that was

mediated by NMDA receptors, did not require L-type CA2+

channels and occurred only when high frequency tetanizing

stimulus trains were used [1168]. OFQ/N antagonizes the

inhibition of CA2+ channels mediated by the mu opioid

receptor [1357]. OFQ/N inhibited glutamate-mediated EPSC

evoked by optic nerve stimulation in the suprachiasmatic

nucleus as well as increasing miniature EPSC frequency

through N-type and P-type Ca(2+) channels without altering

the amplitude of currents induced by AMPA or NMDA [418].

The NOR antagonist, UFP-101 antagonized OFQ/N-induced

GIRK channel activation in a concentration-dependent man-

ner and shifted the concentration–response curve of OFQ/N in

PAG neurons without affecting membrane current per se [212].

OFQ/N produced concentration-dependent inhibition of

Ca(2+) currents in stellate ganglion neurons that was reversed

by a NOR antagonist and by pertussis toxin; the NOR in these

neurons is its short form [1019].

13. General activity and locomotion

Morphine’s biphasic effects on locomotor behavior were

affected by prior morphine tolerance and withdrawal such

that tolerance developed to the inhibitory action of high

morphine doses even 8 weeks after morphine withdrawal,

while tolerance to the locomotor enhancing effect of low

morphine doses was detected 18 h after withdrawal, but not 3

weeks later. The decrease in locomotion caused by sponta-

neous withdrawal was blocked by naloxone and NTI [1187].

Periadolescent exposure to morphine produces greater sub-

sequent morphine-induced locomotor sensitization in adult-

hood [1280]. Morphine respectively decreased and increased

locomotion at low and high doses, whereas rearing and

grooming were decreased at all doses [920]. DA-deficient mice

fail to display morphine-induced activity and display a

rightward shift in morphine analgesia, but show morphine

CPP in the presence of caffeine or 1-dihydroxyphenylalanine

[501]. Behavioral sensitization to morphine’s locomotor

activity and rewarding effects were blocked in cyclin-

dependent kinase 5 KO mice as well as byroscovitine, a

cyclase-dependent kinase 5 inhibitor [845]. Morphine doses

that stimulate locomotion increased NAC extracellular DA in

both DBA/2J and C57BL/6J mice, but this effect was lower in the

dorsal striatum in the former group. NAC and striatal 5-HT

levels were, repectively, increased and decreased by morphine

in C57BL/6J and DBA/2J mice [332]. Morphine-induced locomo-

tion and increases in NAC DA release were blocked by NAC

microinjections of the plasminogen activator inhibitor, PAI-1

and potentiated by an extracellular serine protease tissue

plasminogen activator. NAC plasmin enhanced morphine-

induced NAC DA release without affecting locomotion, and all

three compounds failed to affect morphine analgesia [837].

The behavioral locomotor sensitization and increased NAC

DA release following acute morphine in morphine-withdrawn

rats are reduced by acupuncture [594]. Naloxone reduced the

locomor activation induced by morphine, but not ethanol in

mice bred for high and low sensitivity to ethanol [505].

Sensitization to the locomotor stimulant action of repeated

morphine was inhibited by the synthetic NOR receptor

agonists, Ro64–6198 and Ro65–6570; this inhibition was not

affected by a selective NOR antagonist [627]. Non-habituated

Swiss mice display greater morphine-induced and ampheta-

mine-induced locomotor activity than habituated mice, but

fail to show differences for ethanol- and caffeine-induced

locomotion [915]. D-2 DA receptor KO mice displayed normal

locomotor activity following morphine and food conditioning,

but naloxone failed to reduce spontaneous or food-condi-

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83430

tioned activity in these D2 KO mice, an effect also observed in

Enk KO mice [479]. Morphine-induced locomotor activity and

reward, particularly at high morphine doses are enhanced in

CREB (alphadelta) mutant mice, whereas morphine-induced

thermoregulation is attenuated in these animals, effects not

due to MOR expression changes in the VTA, NAC or

hypothalamus [1246]. Microinjections of PLC gamma-1 into

the rostral and ventral regions of the VTA differentially alter

the behavioral sensitization locomotor responses to morphine

[115].

Ultra-low doses of naltrexone enhanced both acute loco-

motor and chronic sensitization effects of oxycodone on

activity, but reduced oxycodone’s rewarding potency and

subsequent vulnerability to relapse [683]. Oxycodone-induced

hyperactivity and the development and expression of loco-

motor sensitization by oxycodone were blocked by L-tetrahy-

dropalmatine [718]. RB-101 which protects Enk from enzymatic

degradation, increased locomotor activity and antidepressant

effects on the forced swim test, effects potentiated further by

chronic administration of the dopamine D-2 receptor antago-

nist, amisulpride, and modulated by DOR agonists (SNC80) and

antagonists (NTI) [234]. Fentanyl competed with light to

reciprocally block phase shifts of behavioral activity rhythms

by suppressing suprachiasmatic nucleus firing rate and

attenuating light-induced Syrina hamster Period 1 gene

expression during the night [1221]. DPDPE treatment reduced

the ability of shock to inhibit locomotor activity, and it reduced

the subsequent ability of either mild shock or shock cues to

reinstate the locomotor deficits nearly 3 weeks later [484].

Salvinorin A, like U69593 disrupted climbing behavior on an

inverted screen task in mice that was sensitive to NBNI;

remifentanil disrupted this behavior through a mu-mediated

mechanism [339]. Cervical spinal cord compression produced

muscle hindlimb spasticity that was associated with decreased

spinal DYN A(1–17) [299]. Mch1r-deficient mice display

increased wheel running activity particularly on a low-fat diet.

Increasing fat in the diet increases wheel running in Mch1tr KO

and wild-type mice in a naloxone-sensitive manner [1375]. The

inability of repeated nicotine administration to increase

locomotor activity in MOR KO mice was accompanied by a

lack of nicotine-induced neural NOS expression in the striatum

[1324]. Naloxone increased ketamine-induced hyperactivity in

the open field in female rats [1289]. Apomorphine reduced

symptoms of restless legs syndrome in patients in a naloxone-

insensitive manner [1198].

14. Gastrointestinal, renal and hepaticfunctions

The following section will review opioid effects described over

the past year for gastric function (Section 14.1), intestinal

function (Section 14.2), nausea and emesis (Section 14.3),

glucose function (Section 14.4), and renal and hepatic function

(Section 14.5).

14.1. Gastric function

OFQ/N inhibited gastric emptying and increased plasma

corticosterone with the former effect blocked by adrenalect-

omy, glucocorticoid antagonism or CRF antagonism; corticos-

terone restored OFQ/N-induced gastric emptying inhibition in

adrenalectomized animals [134]. A potent NOR agonist, [Arg14,

Lys15]OFQ/N was more effective than OFQ/N itself in

decreasing KCl-evoked amylase secretion from isolated

pancreas, delaying gastric emptying, increasing mean bead

colonic expulsion time, and decreasing gastric acid secretion

in water-loaded rats after pylorus ligature [133]. Gastric lesions

produced by a high dose of ethanol were inhibited by central

and systemic OFQ/N in a NOR antagonist-sensitive manner

[822]. Systemic or ventricular OFQ/N reduced macroscopic or

histological gastric mucosal lesions induced by ethanol, an

effect reversed by atropine, subdiaphragmatic vagotomy,

CGRP antagonism and NOS inhibition [942]. The ghrelin

analogue, RC-1139 reduced gastric ileus induced by morphine

or post-surgical effects [940]. Whereas clonidine-induced

gastroprotection is naloxone-sensitive, clonidine-induced

inhition of gastric emptying was naloxone-insensitive [380].

14.2. Intestinal function

Intestinal inflammation increased the potency of morphine’s

inhibition of GI transit, effects absent in inducible NOS KO

mice or in wild-type mice treated with L-NAME. Intestinal

inflammation increased MOR expression in wild-type, but not

NOS KO mice [941]. Neurogenic circular and longitudinal

muscle contractions of the rat ileum were inhibited by

morphine and DAMGO in a CTP-sensitive manner, by DADL

in a NTI-sensitive manner, and to a lesser degree by U50488H

in a NBNI-insensitive manner [438]. Acupuncture reduced

colonic motility and inflammation in colitic rats in a naloxone-

sensitive manner [593]. Fast EPSPs in the guinea pig ileum

declined by 50% after the first electrical stimulus, but

remained constant for the remainder of stimulation; this

rundown was reduced by nicotinic cholinergic, but not opioid

antagonism [983]. NOR KO mice displayed improvements in

experimental colitis symptoms relative to wild-type mice with

decreased expression levels of mucosal addressin cell adhe-

sion molecule-1 and infiltrating cells [577]. Zymosan-induced

peritonitis increased BEND and DYN levels, increased POMC,

but not pre-DYN levels, and increased MOR, but not KOR [181].

The ability of the peptides NPFF and NPVF to produce colonic

contractions was mediated by NO activity, but not by naloxone

or atropine, and did interact with morphine-induced contrac-

tions [338]. The pro-inflammatory effects of melatonin on

experimental peritonitis in chickens were accompanied by

naltrexone-reversible pro-Enk gene expression in peritoneal

leukocytes [748]. Tachyphylaxis induced by alpha,beta-

methylene ATP in the guinea pig small intestine was

unaffected by naloxone [85]. The crude extract of Mitragyna

speciosa and one of its indole alkaloids, 7-hydroxymitragynine

inhibited electrically stimulated contractions of the guinea pig

ileum in a naloxone-reversible manner [510]. Gastrointesinal

transit was significantly higher using hydrolyzed casein

relative to native casein, a response that was naloxone-

insensitive [801]. Whereas codeine-induced inhibition of

gastrointestinal transit was blocked by alvimopan, a mu

antagonist, the latter accelerated transit in vehicle-treated

subjects [420]. Loperamide blocks bethanechol-induced gall-

bladder contraction, despite higher CCK plasma levels [894].

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3431

The inhibition of transient lower esophageal sphincter

relaxations by electrical acupuncture stimulation was insen-

sitive to naloxone [1384]. Patients treated with opioids for non-

malignant pain who suffered from opioid-induced bowel

dysfunction displayed relief following treatment with alvi-

mopan, an oral peripherally acting MOR antagonist without

showing decreases in pain relief [922].

14.3. Nausea and emesis

An addition of a low dose of naloxone to a bolus morphine

infusion does not improve nausea, pruritus, vomiting or

reduce antiemetic treatment in emergency room patients in

pain [442]. Morphine induces vomiting in dogs, but vomiting

does not increase the likelihood of gastroesophageal reflux

during subsequent anesthesia [1290]. Naloxone, but not the

peripherally acting naloxone methiodide reversed the ability

of electroacupuncture to block retching, vomiting and retro-

grade peristaltic contractions induced by VP in dogs [1167]. A

propofol and remifentanil combination produced less post-

operative nausea and vomiting than a propofol + fentanyl

anesthetic procedure [968]. Diphenhydramine paired with

morphine reduced the latter’s emetic effects without altering

morphine PCA in post-surgical patients [702].

14.4. Glucose function

MOR expression in Xenpus oocytes was activated by DAMGO,

but not glucose, and glucose failed to alter DAMGO-induced

activation [631]. Alloxan-treated diabetic rats display marked

increases in systemic MAP and HR following application of

endomorphin-1, an effect blocked by bilateral vagotomy [711].

Agmatine, a imidazoline receptor ligand, decreased plasma

glucose, but not systolic blood pressure in STZ-induced

diabetic rats, while enhancing both plasma and adrenal

medullary BEND [525]. Hypoglycemia induced by electroacu-

puncture increased plasma insulin and BEND, and was

decreased in STZ-induced diabetic rats and MOR KO mice,

and to a lesser degree by naloxone pretreatment [185].

Increased plasma BEND and decreased plasma glucose were

noted in exercise-trained Zucker rats whose insulin-stimu-

lated glucose disposal rate was reversed to that of sedentary

lean littermate controls, an effect reversed by naloxone and

naloxonazine [1133]. Menk increased haemolymph sugar

levels, decreased carbohydrate and glycogen levels, and

increased phosphorylase activity in the heapatopancreas

and muscle tissue of a rice field crab [600].

14.5. Renal and hepatic function

Chronic morphine and, to a lesser degree, tramadol, sig-

nificantly increased alanine aminotransferase, aspartate

aminotransferase, lactate dehydrogenase, blood urea nitrogen

and creatinin levels in rodent liver and kidney specimens [41].

The non-peptide DOR agonist, DPI-221 increased micturition

intervals in normal rats [506]. U50488H administration into the

magnocellular PVN increased urine flow rate and water

diuresis without changing urinary sodium excretion or

cardiovascular function. In contrast, U50488H administration

into the parvocellular PVN elicited an immediate pressor

response, bradycardia, renal sympathoinhibition and delayed

antidiuresis. Both of these effects were blocked by the KOR

antagonist, NBNI [432]. NBNI did not affect diuresis induced by

hypotonic saline volume expansion, but it decreased RSNA

and correspondingly increased urinary sodium excretion

[431]. The tachykinin-3 agonist, [MePhe]-NKB, respectively,

decreased (topical) and increased (intrathecal) bladder activity

and pressure with the latter effect blocked by intrathecal

naltrexone or NK-3 antagonism [569].

In vitro studies demonstrated the metabolic pathway of the

transformation of morphine to morphinone, a toxic metabo-

lite with steroids with a 17beta-hydroxyl group depressing

metabolite formation [1191]. DOR is expressed by proliferating

bile ductiles in the liver of rats with cholestasis [856].

Pharmacokinetic differences in long-acting naltrexone fail

to occur in patients with mild to moderate hepatic impairment

as compared to controls [1207]. The hyporesponsiveness of the

papillary muscle in cholestatic rats was reversed by naltrex-

one and L-NAME [311]. Multiple mechanisms involving

primarily OATP1A1 and OATP1A4 are involved in the rapid

hepatic uptake of the delta-1 agonist, DPDPE [502]. Tramadol

enhanced hepatic insulin sensitivity through enhancement of

the insulin signaling cascade in the cerebral cortex and

hypothalamus in rats missing 90% of their pancreas [218]. The

relative efficacy of buprenorphine and methadone mainte-

nance therapies were evaluated in opiate-dependent patients

with hepatitis C virus infection and attendant hepatic and

gastroenterological symptoms [1233].

15. Cardiovascular responses

This section will review the work done in the last year on the

role of opioids upon heart rate (Section 15.1), cardioprotection

and ischemic preconditioning (Section 15.2) and blood

pressure (Section 15.3).

Reviews: A review [901] examine the role of angiotensin-

converting enzyme-2 in cardiovascular regulation, and

descrinbes its ability to hydrolyze DYN A(1–13). Another

review [923] examines the role of endogenous opioids in the

triggering of hibernation in animals and relates this to the

protective potential of opioids against ischemia and hypoxia.

15.1. Heart rate

Morphine prolonged the cardiac action potential, hyperpolar-

ized the membrane resting potential and augmented the L-

type Ca2+ current; the latter effect was reversed by NTI and

NBNI, but not by CTOP [1304]. Heatstroke increased core

temperature, intracranial pressure and ischemic markers,

while decreasing MAP, cerebral blood flow and O2 partial

pressure; protection against these effects were observed

following mu, but not delta or kappa antagonist pretreatment

[205]. Shock induced by femur fracture and hemorrhage in

anesthetized rats decreased cardiovascular functions that

were accompanied by increased myocardial delta and kappa,

but not mu opioid receptors. delta and kappa, but not mu

antagonism reversed the decreased cardiovascular function

and increased survival rate after shock [712]. Enk was

immunohistochemically localized on axodendritic synapses

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83432

on negative chronotropic and negative dromotropic vagal

preganglionic neurons in the ventrolateral nucleus ambiguous

that project to the heart [109]. Persistent atrial fibrillation

decreased pro-Enk, POMC and KOR, but not DOR mRNA in

mitochondria [681]. The KOR agonist, U50488H administered

into the PAG decreased heart rate in 1-week-old pups and

increased heart rate in 2-week-old pups, with behavioral

activity increased in both age groups [425]. OFQ/N and

endomorphin-1 administered into the rostral NTS each

increased HR and blood pressure with the former blocked

by a NOR antagonist, but not naloxone, and the latter by

naloxone, but not a NOR antagonist [759]. OFQ/N administered

into the medial NTS produced bradycardia and decreased MAP

and HR, but not tachyphylaxis; this response was blocked by

bilateral vagotomy, a NOR antagonist, GABA-A and GABA-B

antagonists and ionotropic glutamate receptor antagonists

[213]. In contrast, OFQ/N administered into the nucleus

ambiguous elicits tachycardia in the rat [214]. ZP120, a partial

OFQ/N agonist blocked OFQ/N-induced responses on the

mouse vas deferens assay and blocked OFQ/N-induced

bradycardia and hypotension [572]. Whereas ventricular

administration of OFQ/N and three potent analogues produce

cardiovascular depressor responses, water diuresis and

inhibitory RSNA, intravenous administration of the OFQ/N

analogues produced a subtle slow onset hypotension with no

change in HR and water diuresis [571].

Hypovolemic dogs displayed similar reductions in HR and

cardiac index following diazepam paired with either hyfdro-

morphone or oxymorphone [741]. An analgesic dose of

morphine in anesthetized horses failed to alter HR, MAP

and oxygen–carbon dioxide exchange [223]. Butorphanol

appeared to maintain anesthesia better than morphine and

control treatments in ponies with all groups showing similar

decreases in HR [235]. Low frequency magnetic fields trigger

the expression of the cardiac lineage-promoting genes GATA-4

and Nkx-2.5 in mouse embryonic stem cells that is accom-

panied by enhanced pro-DYN gene expression and DYN B

synthesis and secretion [1230]. Inotropic depression in the

guinea pig atrium was produced by Citrus sinensis Osbek leaf

extracts in a naloxone-insensitive manner [877]. The action

potential repolarization in sheep cardiac Purkinje fibers was

unaffected by morphine, an effect different from observed

increases by other drugs of abuse [1072]. Naloxone failed to

affect the increased cardiovascular responses to mild mental

stress in posymenopausal women [708].

15.2. Cardioprotection and ischemic preconditioning

Ischemic preconditioning, insulin and morphine all cause

hexokinase redistribution from the cytosol to the mitochon-

dria of the heart [1389]. The cardioprotective effects of

morphine in the ischemia/reperfusion model were accom-

panied by enhanced myocardial levels of COX-2, PGE2 and 6-

keto-PGF (1-alpha) that was blocked by noncompetitive COX,

COX-2, but not COX-1 inhibition [552]. Ischemic precondition-

ing increased the bioavailability of Menk and Menk-Arg-Phe in

the heart [1331]. Morphine preconditioning prevented simu-

lated ischemia-reperfusion-induced apoptosis through an

Ins(1, 4, 5)P(3) signaling pathway in rat ventricular monocytes

[62]. Morphine enhanced isoflurane-induced postconditioning

against myocardial infarction by activating phosphatidylino-

sitol-3-kinase and MOR thereby reducing apoptotic cell death

and preserving myocardial integrity [1276]. Morphine reduced

infarct size in both the trigger and mediator phases in a

naloxone-sensitive manner by increasing phosphorylation of

the inhibitory protein, kappaB, leading to increased activity of

NF-kappaB [368]. A potent opioid peptide, 20,60-dimethyltyr-

osine-D-Arg-Phe-Lys-NH2 was more effective than morphine

in protecting against myocardial stunning during myocardial

ischemia and reperfusion [1116]. In ischemic preconditioning,

necrosis of the skin flap was reduced by morphine, and this

protextive effect was blocked by naloxone [602]. Spinal

morphine administration after aortic occulusion increases

CSF glutamate levels in a MK-801 reversible manner and

produces spastic paraparesis resulting in dark-stained alpha-

motoneurons [566].

Repetitive short-term immobilization improved heart resis-

tance to the arrhythmogenic action of coronary occulusion and

reperfusion, an effect abolished by mu, but not delta or kappa

antagonists [773]. Remifentanil preconditioning-induced car-

dioprotection was mediated by kappa and delta opioid

receptors [1364]. Fentanyl isothiocyanate, a delta-selective

agonist reduced infarct size when administered before ische-

mia, before reperfusion or after reperfusion, effects abolished

by the PI3K inhibitor, wortmannin [445]. Thaliporphine, like

morphine reduced infarct size and improved pressure devel-

opment in a naltrexone-reversible manner following post-

ischemia reperfusion injury [186]. NO KO mice failed to display

the delta opioid receptor-induced reductions in infarct size

produced by ischemia-induced late preconsditioning [458].

U50488H mimicked both acute and delayed ischemic precon-

ditioning by opening KATP channels and activating PKC [1217].

Both infarct volume and neurological deficits induced by

middle cerebral artery occlusion were attenuated in male,

but not female rats by the kappa agonist, BRL52537 [194]. The

therapeutic cardioprotective effects of U50488H were blocked

by NBNI and paxillane, a K (Ca2+) channel inhibitor; the latter

mediated by downstream PKC activation [152]. U50488H

delayed the onset of electrical uncoupling during prolonged

ischemia, increased formazan content and reduced lactate

dehydrogenase, effects sensitive to NBNI and a selective

mitochrondrial ATP-sensitive K(+) channel blocker [193].

Cholestatic liver disease increased susceptibility to ischemia/

reperfusion-induced bradycardia and hypotension, an effect

reversed by naltrexone [465]. Plasma from hibernating wood-

chucks reduced hypoxic damage in swine muscle caused by

ischemic-reperfusion injury in a naloxone-sensitive manner

[508]. Ischemic wounds in rats are healed quicker following

topical opioid agonist treatment by increasing nuclear density

in granulation tissue and increasing angiogenesis [946].

Testicular torsion produced ischemia and morphine lowered

testicular malondialdehyde levels in a naloxone-reversible

manner [1030]. Focal cerebrocortical ischemia and stimulation

of entorhinal afferents induces MOR expression in hippocam-

pal dentate gyrus granule cells [1132].

15.3. Blood pressure

Pressor responses to sciatic nerve stimulation were signifi-

cantly reduced by mu and kappa, but not delta opioid

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3433

antagonists administered into the contralateral, but not

ipsilateral paratrigeminal nucleus; systemic capsaicin abol-

ished the antagonist-induced effects [613]. Morphine pro-

duced naloxone-sensitive relaxation responses in small

mesenteric arteries in the presence and absence of endothe-

lium [897]. Whereas Enk accentuates superior mesenteric

artery hypoperfusion-induced increases in plasma NO, block-

ade of cardiovascular DOR improved hemodynamics, pre-

vented shock irreversibility and reduced plasma NO levels

[159]. Whereas Menk produces a naloxone-reversible vasode-

pressor effect, chimeric peptides of Menk and FMRFa produce

a fall in MAP and HR that is only partially antagonized by

naloxone [471]. BEND decreased systemic vascular resistance,

blood pressure and plasma levels of NE and endothelin-1 in

hypertensive subjects; all effects were blocked by naloxone

[241]. The delta agonist, Delt administered after hemorrhage,

led to a faster recovery of MAP, and a stabilization of HR [785].

Endomorphin-2 into the rostral ventolateral medulla

decreased MAP and HR through a non-vagal, but mu-1-

sensitive mechanism. An endomorphin analogue, [TIC4]-

endomorphin enhance vasorelaxation of rat aortic rings

[1370]. Electroacupuncure administered to the lower leg, but

not back reduced increased MAP induced by rectal distension

in a naloxone-sensitive, but naloxone methiodide-insensitive

manner [536]. Naloxone ameliorated the hypotensive and

bradycardiac effects of lipopolysaccharide by reducing the

elevated levels of serum glutamate-oxalacetate transaminase

and glutamate-pyruvate transaminase [701]. Unilateral sti-

mulation of the aortic nerve elicited depressor and bradycar-

dic responses that were reduced by endomorphin-2, and

reversed by naloxonazine [575]. Endomorphin-1[psi] and

endomorphin-2[psi] analogues of endomorphins produced

vasorelaxant responses in rat aorta rings in a manner more

sensitive than the parent peptides and blocked by opioid and

NO antagonism [348]. OFQ/N administered into the rostral

VLM blocked the pressor response induced by gastric disten-

sion. Electroacupuncture produced a similar effect that was

blocked by a NOP antagonist, but not naloxone, and that was

reinstated by a mu agonist administered into the rostral VLM

[243]. Plasmapheresis increases plasma BEND levels after the

first session, but not thereafter [84].

16. Respiration and thermoregulation

16.1. Respiration

beta-Arrestin KO mice display marked reductions in mor-

phine-induced respiratory depression and acute constipation,

while displaying prolonged morphine-induced analgesia [963].

Morphine dose-dependently reduced pulmonary oedema

induced by alpha-naphthylthiourea as well as inducible

NOS immunoreactivity in the lung with both effects blocked

by the peripheral opiate antagonist, naloxone methiodide

[230]. Morphine-induced reductions in the minimum alveolar

anesthetic concentration by isoflurane were blocked in a

concentration-dependent manner by nitrous oxide [1040].

Whereas morphine and the mu opioid agonist, [Dmt(1)]-

DALDA reduced respiratory frequency and minute volume in a

naloxone-sensitive manner, the former increased tidal

volume where the latter agonist decreased it [1075]. The

ability of morphine to arrest the external rhythm of the pre-

Botzinger complex in the rat and the lung oscillator in the frog

failed to affect the pre-inspiratory oscillators in the rat or the

frog [1226]. DAMGO and SP each modulate the pre-Botzinger

respiratory rhythm generator as early as embryonic day 15 in

the mouse [1184]. Morphine impairs host innate immune

responses to TNF-alpha, interleukin-1 and -6 in the lung and

increases susceptibility to Streptococcus pneumoniae lung

infection in mice [1257]. Codeine suppressed the ability of

microstimulation of the NTS or superior laryngeal nerves to

produce an inspiratory discharge of the phrenic nerve

immediately followed by a large burst discharge of the

iliohypogastric nerve [871]. Bilateral midcervical vagotomy

significantly reduced the ability of morphine to prolong

expiratory respiration and decrease MAP with naloxone

bringing any morphine effects back to control levels [563].

Hypoxia induced catecholamine secretion from the adrenal

medulla was not blocked by opioid agonists [997]. DAMGO

transformed the burst pattern of post-inspiratory neurons into

that of pre-inspiratory neurons in the rostral pons of the

newborn rat [610]. DOR-induced protection against hypoxia

was stronger than that of glycine, GABA and taurine [1369].

DAMGO also facilitated the respiratory rhythm in a newborn

rat pons-medulla-spinal cord preparation [1156]. Endomor-

phin-1 and -2 were less potent than morphine and DAMGO in

attenuating a hypercapnic CO(2)-induced ventilatory response

with all four agonist effects blocked by naloxone, but not

peripherally acting methyl-naloxone [247]. Menk reduced

histamine-induced bronchoconstriction in guinea pigs

[1188]. Hypoxic preconditioning increased DOR mRNA and

reversed Lenk-induced reductions observed by severe

hypoxia, effects blocked by DOR antagonists [737]. The DA

D-1 antagonist, SCH23390 slowed respiratory activity by

prolonging the inspiratory and expiratory phases, and

enhancing the respiratory depressant actions of fentanyl

[654]. Naloxone-sensitive respiratory depressive and analgesic

effects of morphine failed to be affected by the 5-HT-4 receptor

agonist, mosapride [729]. The minimum alveolar concentra-

tions following volatile anesthetics like halothane, isoflurane

and sevoflurane were identical in wild-type and NOR KO mice

[497]. OFQ/N and a more potent NOR agonist inhibited in a

NOR-selective manner bronchoconstriction and plasma extra-

vasation in the bronchi and trachea of rabbits treated with a

combination of propranolol, atropine and phosphoramidon,

but not a similar response produced by SP [248]. OFQ/N and an

agonist also inhibited electrical field stimulation-induced

contractions of human bronchi tissue in a naloxone-insensi-

tive, but UFP-101-sensitive manner [70].

A retrospective case control analysis of post-operative

naloxone-reversible respiratory events indicated that over

three-fourths occurred within 24 h after surgery with such risk

factors as age, chronic obstructive pulmonary disease, and

placed on hydromorphone [1171]. M6G produced reduced

analgesia, but normal respiratory depressive responses in

volunteers with a polymorphism of the MOR gene (OPRM:

c.118A > G) relative to those without the genotype [1007].

Hopoxemia occurred on the second, but especially the third

post-operative night following thoracic epidural analgesia in

patients undergoing elective coronary bypass surgery [733].

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 83434

Oxycodone produced more prolonged respiratory recovery

from hypoxaemia and hypercapnia than morphine in healthy

subjects [650]. A correlation was found between intraoperative

fentanyl administration and post-operative respiratory

depression [1063]. Hypoxia-inducing factor-1 is activated by

hypoxia, and this activation is unaffected by pretreatment

with mu, delta or kappa opioid receptor agonists [1147]. The

peripheral opioid agonist, frakefamide produced transient

myalgia in healthy human volunteers, but, unlike morphine,

did not produce any central respiratory depression [811].

Diamorphine significantly reduced breathlessness and mean

heart rate in elderly subjects with respiratory problems [18].

Continuous morphine infusion decreased plasma NE concen-

trations in ventilated newborns, consistent with morphine-

induced decreases in stress responses [1086], but did not

improve short-term pulmonary outcomes among ventilated

preterm neonates suffering from respiratory distress syn-

drome [93]. Opioid treatment during neonatal asphyxiation at

term produced less brain injury and better long-term

neurologic outcomes [30]. Narcotic administration and ste-

nosing lesions of the upper airway resulted in respiratory

compromise and death [142].

16.2. Thermoregulation

Placing Syrian hamsters in a cold room on short day-light/

dark cycle induced hibernation and reductions in central body

temperature. Naloxone and naloxonazine, but not naltrindole

or NBNI elevated temperatures in hibernating hamsters

during the entrance and maintenance phases [1155]. Activa-

tion of GIRK-2-containing potassium channels appears

important for hypothermia in duced by mu, delta and kappa

opioid receptors as well as other receptor systems [237].

Ventricular fentanyl increases brown adipose tissue, sympa-

thetic nerve activity and brown adipose tissue temperature in

a naloxone-reversible manner with inhibitory glycine admin-

istration into the rostral raphe pallidus and rostral VLM

blocking these hyperthermic responses as well [156]. The

delta agonist, SNC-80 produced hypothermia that was

blocked by naltrexone and the delta-2 antagonist, naltriben,

but not the delta-1 antagonist, BNTX [976]. Peripheral

administration of the kappa opioid agonist, ICI204448 elicits

hypothermia in cold-exposed rats, an effect that was not

blocked by central NBNI [975]. Naltrexone protected against

hyperthermia, hypotension and BEND overproduction in rats

exposed to heatstroke [516]. Whereas NBNI-induced

hyperthermia was blocked by the mu antagonist, CTAP,

CTAP-induced hypothermia was blocked by the kappa

antagonist, NBNI [202]. A selective NOR agonist, W-212393

significantly accelerated the re-entrainment of body tem-

perature rhythm to a 6 h advanced light–dark cycle presum-

ably by inducing a phase advance in circadian rhythms by

suppressing spontaneous firing at rat suprachiasmatic

nucleus neurons [1180]. Spinal anesthesia with bupivacaine,

morphine and fentanyl delivered to women undering caesar-

ean delivery produced hypothermia that was reversed by

lorazepam [494]. Intrathecal morphine was less effective than

pethidine in reducing the incidence and intensity of shivering

when added to hyperbaric bupivacaine after caesarean

delivery [509], but a combination of fentanyl, bupivacaine

and morphine was effective in reducing shivering after

caesarean section [1172].

17. Immunological responses

A review [477] summarizes a role for DYN in protection and

proapoptotic actions in neurons and glia in which increased

pro-DYN gene expression is observed in some disease states

and disruptions in DYN processing, particularly the produc-

tion of some DYN derivatives, can accompany pathophysio-

logical situations. A second review [478] summarizes the

molecular targets of opiate drug abuse in neuroAIDS. Another

review [900] examines the immunological effects of acute and

chronic opiate treatment in the presence and absence of pain.

Morphine potentiates HIV-1 gp120-induced neuronal apop-

tosis through activation of the p38 MAPK intracellular

signaling pathway [514], and inhibits CD8+ T-cell-mediated

noncytolytic anti-HIV activity in latently infected immune

cells [1261]. Morphine-dependent monkeys displayed

increases of the replication rate of the simian AIDS virus

SIV, mac239 [221]. Morphine and administration of HIV-1 Tat

produce synergistic increases in intracellular Ca2+, and the

release of MCP-1, RANTES and interleukin-6 from mouse

astrocytes [314]. Morphine down-regulates gene expression of

the beta-chemokines, MCP-1 and MIP-1 beta while up-

regulating their specific receptors, CCR2b, CCR3 and CCR5

[745], and exacerbates HIV-1 viral protein gp120-induced

modulation of chemokine gene exprexxion in U373 astro-

cytoma cells [744]. Morphine withdrawal enhances hepatitis C

virus replicon expression [1251]. Patients undergoing caesar-

ean delivery and receiving intrathecal morphine and PCA

displayed increased reactivation of herpes simplex labialis

[265].

Morphine induced morphological changes in cultured

microglia from a globular or bipolar rod-like shape to a flat

and lamellipodial shape as well as increased gene expression

of BDNF in a naloxone-sensitive and wortmannin-sensitive

manner. MOR AS probes blocked the morphological changes

[1150]. Chronic morphine up-regulated glial fibrillary acidic

protein in a yohimbine-sensitive manner in the VTA, NAC and

frontal cortex [396]. Chronic morphine also promoted specific

Th2 cytokine production by murine T-cells through a Fas/Fas

ligand-dependent mechanism [439], and morphine withdra-

wal contributed to Th cell differentiation by biasing cells

toward the Th2 lineage [584]. Chronic morphine produced

spinal apoptosis that was blocked by an adenylyl cyclase

inhibitor, a PKA inhibitor or a MAPK inhibitor [695]. Morphine

activated activity-regulated cytoskeleton-associated protein

in murine striatum and neuroblastoma cells expressing MOR

[1381]. Morphine’s ability to zymosan-induced leukocyte

accumulation during peritonitis was accompanied by an

enhanced release of Menk content in peritoneal fluid and

release from exudatory leukocytes, but inhibited Menk

fluctuations in hypothalamus and striatum [180]. The 50 flank

sequence of the MOR gene is a potential promoter region in

human lymphocytes [1273], and morphine enhanced human

cytotoxic T-lymphocytes against leukemia cell lines without

affecting natural killer cell activity [373]. However, morphine

failed to alter cell expression of some apoptosis-related

p e p t i d e s 2 7 ( 2 0 0 6 ) 3 3 9 1 – 3 4 7 8 3435

molecules in cultured human lymphocytes [870]. Morphine

suppressed splenic T-cell proliferation after burn injry by

increasing NO and an immunosuppressive Th-2 phenotype

[16]. In the spleens of herpes simplex virus-infected mice,

morphine increases interferon-beta and -alpha mRNA, but

suppresses interferon-gamma and interleukin-12; RU486

blocked morphine’s effects on interferon-beta and -gamma

[1071]. Immunosuppression induced by abrupt morphine

withdrawal is mediated by splenic macrophages and B cells

[964]. The increased sensitivity of morphine-withdrawn mice

to Salmonella enterica serovar Typhimurium is associated with

interleukin-12 suppression [347]. Morphine-withdrawn mice

display sensitization to lipopolysaccharide that is related to

increased NO and TNF-alpha and decreased interleukin-12

[346] levels. Morphine induces CD4+ T-cell interleukin-4

expression through an adenylyl cyclase mechanism that acts

independently of PKA activity [1016]. Acetylsalicylic acid, but

not morphine reduces thalamic mast cell numbers [309].

BEND ameliorates synovial cell dysfunction in the collagen-

induced arthritis model by specific down-regulation of NF-

kappaB activity [1322]. BEND administration on the 19th day of

pregnancy increased serotonin content in peritoneal and

blood lymphocytes and mast cells in the F1 generation, but

reduced serotonin content in mast cells in the F2 generation

[245]. BEND alleviates collagen-induced arthritis by depressing

spleen Th1 responses and down-regulating proinflammatory

and other rheumatic factors [1321]. BEND also stimulated

interleukin-1-beta and TNF-alpha expression in cultured

human articular chrondocytes in a naltrexone-sensitive

manner [27]. A fluorescein isothiocyanate-conjugated naltrex-

one could only stain opioid receptors expressed on lympho-

cytes using an indirect biotin-streptavidin amplification

procedure [573]. Whereas peripherally acting naloxone

methiodide decreased interleukin-1-beta-induced Fos activity

in the medial PVN CRF neurons and increased Fos in

ventrolateral medullary epinephrine cells and NTS NE cells,

centrally acting naloxone produced decreases in the PVN,

ventrolateral medulla and NTS, but increased Fos in the

central amygdala and BNST [139]. Chronic ethanol reduced

basal and BEND-induced levels of cytolytic factors in splenic

rat NK cells [296]. Splenocyte proliferations were inhibited

by methadone in concentration-dependent fashion, by fenta-

nyl in a bell-shaped curve, and were induced in concentration-

dependent fashion by NBNI [523]. The delta agonist, SNC-80

as well as naltrindole- and naltrexone-derived agonists

stimulated lymphoproliferation of resident and concanava-

lin-treated lymphocytes [147]. Loperamide improved inter-

leukin-6-induced inhibition of insulin signals in myoblast

C2C12 cells [1209]. Tramadol fails to impair the phagocytic

capacity of human peripheral blood cells, whereas morphine

reduced phagocytosis [78]. Leumorphin, but not other pro-

DYN gene products increased cell viability in PC12 cells

through a naloxone-insensitive and NBNI-insensitive

mechanism, but sensitive to phosphatidylinositol 3-kinase

and MAPK pathways [666]. OFQ/N and some of its analogues,

including Ro64–6198 stimulate human monocyte chemotaxis

through a naloxone-insensitive, but a UFP-101-sensitive

mechanism [1199]. General, mu and delta antagonists

increased cell proliferation in immature adrenals, and

decreased it in regenerating glands effects reversed by mu

and delta agonists [750]. Activation of mu, delta and kappa

receptors induce phosphorylation of tuberin in transfected

HEK293 cells [1296].

Rat mammary cancerous tumors induced by N-methyl-

nitrosourea increased plasma enkephalin-degrading tyrosyl

aminopeptidase [162], but decreased it in hypothalamus,

anterior and posterior pituitary, thyroid and ovary [163],

suggesting involvement of Enk levels during breast cancer

development. Endomorphin-1 and endomorphin-2 show high

affinity for the MOR present in mouse mammary adenocarci-

noma [1285], and endomorphin-2 showed greater binding

affinity than morphiceptin [354]. Squamous cell carcinomas of

the head and neck were delayed by pretreatment with opioid

growth factor, but not by the cytotoxic inhibitor of cell

proliferation, paclitaxel, but tumor weights were only reduced

by a combination of opioid growth factor and paclitaxel [541].

These carcinomas were best treated by a combination of

opioid growth factor and paclitaxel with the former naloxone-

sensitive and more effective than other endogenous opioids

[790]. Gemcitabine chemotherapy and opioid growth factor

biotherapy enhance growth inhibition of pancreatic adeno-

carcinomas [1336]. Inhibition by opioid growth factor and

stimulation by naltrexone on cell growth in tissue culture are

not due to alterations in differentiation pathways [1337]. Gene

transfer of opioid growth factor receptor cDNA increased cell

proliferation of the corneal epithelium [1339]. Naloxone failed

to alter the midazolam-induced decreases in O(2)(�) and

H(2)O(2) formation and released myeloperoxidase in neutro-

phils [830].

Low and high doses of morphine respectively augment and

inhibit the production of Leishmania donovani amastigote

component-induced colony-stimulating factor by mouse

peritoneal macrophages [1090]. Restraint stress suppressed

splenic CD3(�)DX5+ cellularity and NK cytolytic activity

induced by administration of an influenza virus in mice with

the latter effect blocked by general and mu, but not delta or

kappa opioid antagonists [1201]. Menk-affected antioxidant

enzyme activity of red blood cells is observed to the greatest

degree at the reproductive age in mouse macrophages and

human neutrophils [1106]. The ability and effectiveness of

Menk to produce anti-tumor activity varied as a function of the

culture medium in which the in vitro assays were conducted

[412]. Delt-Dvariant inhibits p38MAPK and suppresses activa-

tion of murine macrophages while dose-dependently reducing

TNFalpha and MIP-2 production [522]. Fever elicited by

interleukin-1 beta was mimicked by the 5-HT-2 agonist, DOI

with both responses were blocked by MOR or 5-HT-2 receptor

antagonists [211]. The increased release of glutmate and

aspartate from astrocytes following TNF-alpha administration

is blocked by both morphine and naloxone [1303].

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Endogenous opiates and behavior: 2005

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