New Chimica Farmaceutica e Tossicologica –Parte IImms.dsfarm.unipd.it/files/Lezioni/CFTII/PDF/CFTII... · 2017. 8. 14. · Chimica Farmaceutica e Tossicologica –Parte II M S.MORO
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
Parte IParte I
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
Pain, the experience of hurting or soreness, is generally classifiedinto four broad categories which are differentiated according to thesource of pain. The categories include:
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
Glutammic acid Substance P
1. Pain and Narcotic Analgesics1. Pain and Narcotic AnalgesicsThe importance of the descending monoamine systemfor the painexperience and its treatment:
Each family derives from a distinct precursor protein and has acharacteristic anatomical distribution. Each precursor is subject tocomplex cleavages and post-translational modifications resulting in thesynthesis of multiple active peptides.
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.3 Opioid receptors distribution and site effects
Opioid use carries several side effects.These include drowsiness, nausea, slowerbreathing, and a general depression of therespiratory system. Further, opioidsoften cause constipation, or opioid -
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
often cause constipation, or opioid -induced constipation (OIC). OIC is anuncomfortable side-effect that occurs inmany patients who receive opioidtreatments to relieve pain.
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.3 Opioid Receptors: physiological effects
(1) Analgesia, euphoriant, respiratory depressant, and physicaldependence properties of morphine result principally fromactions at mu receptors (MOR). Stimulation of mu 1-receptorsblocks pain while stimulation of mu 2-receptor causesrespiratory depression and constipation .
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.3 Opioid Receptors: cellular actions
Opioids act at two sites:
1. They reduce pain signal transmission byactivation pre-synaptic opioid receptors. Thisleads to reduced intracellular cAMPconcentration, decreased calcium ion influxand thus inhibits the release of excitatory
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
2. At the post-synaptic level, opioid-receptor binding evokes ahyperpolarisation of the neuronalmembrane which decreases probability ofthe generation of an action potential.
and thus inhibits the release of excitatoryneurotransmitters (glutamate, substance P).
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.3 Opioid Receptors: Tolerance and physical dependence
(1) Tolerance : with frequently repeated administration oftherapeutic doses of morphine or its surrogates, there is agradual loss in effectiveness. To reproduce the originalresponse, a larger dose must be administered.
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
Papaver somniferumMorphine was the first pharmaceutical isolated from a natural product by 1820. Morphine salesbegan in 1827, by Heinrich Emanuel Merck of Darmstadt, and helped him expand hisfamilypharmacy into the Merck KGaA pharmaceutical company.
alkaloids by weight, dependingon the variety.The chief alkaloids are Morphine (4-21%),Codeine (0.8-2.5%), Thebaine (0.5-2%),Papaverine (0.5-2.5%), Noscapine (4-8%),Meconic Acid (3-5%).
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.4 Opiates and Opioids: definitions
Opiates:alkaloids derived from the opium poppy(Morphine, Codeine, Thebaine…)
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
O OOH H
2
3 4 5 6
712 13
14
O OOH H
2
3 4 5 6
712 13
14
No activity… at least at SNC!!!
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.4 Morphine:
HN
CH3
1 89
10
1114
15
16
17
Morphine presents difficulty ingaining access to the brain appears tobe greatest with amphorteric agents(ie., drugs possessing both acidic [aphenolic hydroxyl at C3] and basicgroups[the N17 amine]). Heroin and
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.4 MorphineIt has been unequivocally shown that human neuroblastoma cells areable to synthesize morphine.The metabolic route starting from L-tyrosine involving at least 19 chemicalsteps shares remarkable similarities with the morphine biosynthesis in opiumpoppy.In the future, the identification of the respective genes and enzymes inhumans and animals will provide information on the evolution of this pathway
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
humans and animals will provide information on the evolution of this pathwayin the animal kingdom. The function of endogenous morphine is still a matterof discussion. In contrast to plants, where morphine is a highly specificsecondary metabolite providing protection against herbivores, presumptionsindicate that morphine in animals and humans may play a role as a generalregulator and/or transmitter. Once these functions are identified, the genesand enzymes of morphine biosynthesis may become attractive targets for themodulation of pain, immune response, cell death, and behaviouralphenomena.
Boettcher C et al. PNAS 2005;102:8495-8500
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
Boettcher C et al. PNAS 2005;102:8495-8500
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.5 Codeine
HN
CH3
1 89
10
11
1415
16
17Codeine, or methylmorphine, is anatural alkaloid found in opiumpoppy.Codeine was first isolated in 1832 inFrance by Pierre Robiquet, a Frenchchemistand pharmacistalreadyfamous
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
Codeine(5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy
-17-methylmorphinan-6-ol
O OOCH3 H
2
3 4 5 6
712 13
14 chemistand pharmacistalreadyfamousfor the discovery ofalizarin, the mostwidespread red dye, while working onrefined morphine extraction processes.Codeine is currently the most widelyused opiate in the world, and probablythe most commonly used drug overall.
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.5 Codeine
HN
CH3
1 89
10
11
1415
16
17
Codeine is partial agonist for mu anddelta opioid receptors.It is one of the most effective orally-administered opioid analgesics and has awide safety margin. Its strength rangesfrom 8 to 12 percent of morphine inmost people. Codeine is considereda
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
Codeine(5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy
-17-methylmorphinan-6-ol
O OOCH3 H
2
3 4 5 6
712 13
14 most people. Codeine is consideredaprodrug, since it is metabolisedin vivoto the primary active compoundsmorphine (5-10%) and codeine-6-glucuronide (≅ 70%).
logP = 1.2
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
O OOCH3 H
2
3 4 5 6
712 13
14
P450 2D6H-O
Morphine
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.5 Codeine… and its metabolism!
The metabolism rate is approximately 30mg of codeine in an hour and about 90%of the drug will be excreted from the bodywithin a day. In most people,only about
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
Codeine in conjunction with anti-nausea medication promethazine inthe form of the syrup has become one of the most abused codeinepreparations. Although there are various forms of this syrup varyingin strengths, the “purple” version is highly publicized andis the mostsought after. In this form, 60mg of codeine per liquid ounce is usedwhich makes it the strongest of the codeine syrups. This “PurpleDrank” is frequently referenced and praised in the southernrap andHouston-based hip-hop community where it is mixed with the softdrink Sprite.
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.5 Codeine as antitussive?
Codeine for acute cough in children
QUESTION Owing to Health Canada’s recent recommendations to avoid the useof over-the-counter cough and cold medications in preschool children, I waslooking at other antitussive medications for acute cough. Codeine wasrecommended in the past for this indication. What is the evidence for its useandhoweffectiveandsafeis it?
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
howeffectiveandsafeis it?
ANSWER Cough is one of the most common symptoms in children, and theopioid codeine has known antitussive qualities mediated bya central nervoussystem pathway. However, current evidence finds codeine to be no moreeffective than placebo for acute cough in children. Its safety profile and recentadvances in understanding codeine’s variable effectiveness prohibitrecommending codeine for cough in children.
Goldman, RD "Codeine for acute cough in children". Canadian Family Physician 56 (12): 1293–4 (2010).
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.5 Codeine in combination with…
Codeine is marketed as both a single-ingredient drug and in combinationpreparationswith Paracetamol, with Aspirin ; with Ibuprofen or Naproxen orDiclofenac or Indomethacin. These combinations provide greater painreliefthan either agent alone (drug synergy).
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.5 Heroin
HN
CH3
1
2 7
89
10
11
12 13
1415
16
17
Heroin, or diacetylmorphine, also known asdiamorphine, is a semi-synthetic opioid drugsynthesized from morphine.
The German drug company Bayer named its newover the counter drug "Heroin" in 1895. Thename was derived from the German word"heroisch" (heroic) due to its perceived "heroic"effects upon a user. However it was chiefly
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
Heroin(5α,6α)-7,8-didehydro- 4,5-epoxy-
17-methylmorphinan- 3,6-diol diacetate
O OO
O
O3 4 5 6
12 13 effects upon a user. However it was chieflydeveloped as a morphine substitute for coughsuppressants that did not have morphine'saddictive side-effects; morphine at the time was apopular recreational drug so Bayer wanted to finda similar but non-addictive substitute to market.However, contrary to Bayer's advertising as a"non-addictive morphine substitute," heroinwould soon have one of the highest rates ofdependence amongst its users
logP = 1.6
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
Heroin was originally marketed as a cough suppressant in 1898. It was, at the time,believed to be a non-addictive alternative to other opiate-containing cough syrups. Thiswas quickly realized to be not true as heroin readily breaks down into morphine in thebody. Morphine was already known to be addictive,.
O OO
HN
CH3
O
O
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.6 Dihydromorphine
HN
CH3
1 89
10
1114
15
16
17
Dihydromorphine is a semi-syntheticopioid invented in Germany in 1900. Instructure, it is very similar to morphine,the only difference being the reduction ofthe double bond between positions 7 and8 in morphine to a single bond.
14 8 in morphine to a single bond.Dihydromorphine can be made by severalprocesses, including hydrogenatingmorphine.Dihydromorphine is slightly stronger thanmorphine as an analgesic with a similarside-effect profile.
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
O OO CH3H3C
Thebaine
Thebaine is not used therapeutically, but as the main alkaloid extracted fromPapaver bracteatum(Iranian poppy), it can be converted industrially into a variety of compounds including Oxycodone,Oxymorphone, Nalbuphine, Naloxone, Naltrexone, Buprenorphine andEtorphine.
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
Buprenorphine is a derivative of the opioid alkaloid thebaine that is a more potent (25 – 40 times)and longer lasting analgesic than morphine. It appears to act as apartial agonist at mu andkappaopioid receptors and as an antagonist at delta receptors. The lack of delta-agonist activity hasbeensuggested to account for the observation that buprenorphine tolerance may not developwithchronic use.
O OO CH3H3C
Thebaine Buprenorphine
O OO OCH3
H H
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
Naloxone is a drug used to counter the effects of opioid overdose, for exampleheroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory system. Itis marketed under various trademarks including Narcan®.
O OOH O OOHOxymorphone Naloxone
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
O OOH H
2
3 4 5 6
712 13
14
5 rings
OH
4 rings(morphynan)
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
2.1 Levorphanol
HN
CH3Levorphanol is an opioid medication usedto treat severe pain.Levorphanol has the same properties asmorphine with respect to the potential forhabituation, tolerance, physical dependenceandwithdrawalsyndrome. It is 4 to 8 times
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
OH
(-)-17-methylmorphinan-3-ol
andwithdrawalsyndrome. It is 4 to 8 timesas potent as morphine and has a longerhalf-life.Levorphanol has affinity toμ, κ, and δopioid receptors.
logP = 3.1pKa = 9.6
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
2.1 Dextromethorphan
Dextromethorphan is the dextrorotatoryenantiomer ofLevomethorphan, which isthe methyl ether ofLevorphanol, both opioidanalgesics. Dextromethorphan is anantitussive (cough suppressant)drug. It
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
(+) 17-methylmorphinan-3-methoxy
antitussive (cough suppressant)drug. Itshows high affinity binding to several regionsof the brain, including the medullary coughcenter. It is one of the widely usedantitussives.
logP = 3.6pKa = 9.7
OCH3
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
CYP2D6
OCH3OH
Dextrorphan (+)-17-methylmorphinan-3-ol
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1.5 Dextromethorphan/Dextrophan as antitussive?
A 2004 studies conducted by the American Academy of Pediatrics showthat dextromethorphan is NOT superior to a placebo in providingnocturnalsymptomrelief for childrenwith coughandsleepdifficulty due
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
nocturnalsymptomrelief for childrenwith coughandsleepdifficulty dueto upper respiratory infections.
Paul IM, Yoder KE, Crowell KR, Shaffer ML, McMillan HS, Carlson LC, Dilworth DA, Berlin CM (2004). "Effect ofDextromethorphan, Diphenhydramine, and Placebo on Nocturnal Cough and Sleep Quality for Coughing Children and TheirParents".Pediatrics114 (1): e85–90.
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
2.2 Levallorphan
HN
Levallorphan is a drug of the morphinanfamily which is used as an opioid antidote orantagonist. It acts as aμ-opioid receptor weakpartial agonist, and as a result, blocks theeffects of stronger agents with greater intrinsicactivity such as morphine or endogenousβ-endorphin.
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
OH
Levallorphan was formerly widely used ingeneral anesthesia, mainly to reverse therespiratory depression produced by the opioidanalgesics and barbiturates which are used forinduction of surgical anaesthesia, although it isnow less common as the newer drug naloxonetends to be used instead.(-)-17-allylmorphinan-3-ol
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
OH4 rings
(morphynan)3 rings
(benzomorphan)
OH
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
2.4 Pentazocine
N
CH3
CH3
Pentazocine is a synthetically-preparedprototypical mixed agonist-antagonistnarcotic (opioid analgesic) drug of thebenzomorphan class of opioids used to treatmild to moderately severe pain.It exists in two stereoisomers designated (+)and (-) that have radically different effects onopioid receptors. (-)-pentazocineis a kappa-
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
O
CH3
CH3
H
opioid receptors. (-)-pentazocineis a kappa-opioid receptor agonist; (+)-pentazocine is anon-opioid sigma receptor agonist but is notan agonist at the kappa receptor. The (+)-pentazocine stereoisomer partially blocks theanalgesic effects of morphine ostensibly atthe mu receptor.The kappa receptor agonism of the (-) isomeris analgesic.
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
PhenylPiPeridines (PPPs)
OH
Meperidina PEPAP
Prodine
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
2.6 Fentanyl
N N
O Fentanyl is a synthetic primaryμ-opioid agonist and a potent narcoticanalgesic with a rapid onset and shortduration of action. Fentanyl isapproximately 100 times morepotent than morphine.Fentanylwasfirst synthesizedby Paul
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
Remifentanyl
Sufentanyl
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
2.7 Carfentanil
NN
O
O
O
Carfentanil is an analogue of thepopular synthetic opioid analgesicfentanyl, and is one of the most potentopioids known (also the most potentopioid used commercially).Carfentanil was discovered in 1976 byJanssen Pharmaceutica. It has a
Janssen Pharmaceutica. It has aquantitative potency approximately10,000 times that of morphine and 100times that of fentanyl. It is marketedunder the trade name Wildnil as atranquilizer for large animals.
logP = 4.0
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
2.8 TramadolTramadol, a centrally-acting analgesic, exists as aracemic mixture of thetrans isomer, with importantdifferences in binding, activity, and metabolismassociated with the two enantiomers. Although itsmode of action is not completely understood, fromanimal tests, at least two complementary mechanismsappear applicable: binding of parent and M1metabolite toμ-opioid receptors and weak inhibitionof reuptakeof norepinephrineand serotonin. Opioid
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
of reuptakeof norepinephrineand serotonin. Opioidactivity is due to both low affinity binding of theparent compound and higher affinity binding of the O-demethylated metabolite M1 toμ-opioid receptors. Inanimal models, M1 is up to 6 times more potent thantramadol in producing analgesia and 200 times morepotent inμ-opioid binding. Opiate antagonist naloxoneonly partially antagonized tramadol-induced analgesia.
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
2.8 Tramadol: methabolism
Hepatic. The major metabolic pathwaysappear to be N- and O- demethylation andglucuronidation or sulfation in the liver.One metabolite (O-desmethyltramadol,denoted M1) is pharmacologically active inanimal models. CYP3A4 and CYP2B6facilitatesthebiotransformationof tramadol
Loperamide is an opioid receptor agonist and acts on the mu opioid receptors in themyenteric plexuslarge intestines;it does NOT affect the central nervous systemlikeother opioids.. It works specifically by decreasing the activity of the myenteric plexuswhich decreases the motility of the circular and longitudinal smooth muscles of theintestinal wall.
intra 1-4 hydrogen bondboat conformation selection
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
Loperamide is one of the long-acting syntheticantidiarrheals; it is not significantlyabsorbed from the gut, and has no effect on the adrenergic system or central nervoussystem. In fact, Loperamide is asubstrate of P-glycoprotein (P-gp), therefore theconcentration of Loperamide will increase when given with aP-Glycoprotein inhibitor.Common P-Glycoprotein inhibitors includequinidine, ritonavir, and ketoconazole,among others. Loperamide is also capable of decreasing the concentration of other P-Glycoprotein substrates. As an example, whensaquinavirconcentrations can decrease byhalf when given with loperamide.
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
P-gp is extensively distributed and expressed in theintestinal epitheliumwhere it pumpsxenobiotics (such as toxins or drugs) back into the intestinal lumen, inliver cellswhereitpumps them into bile ducts, in the cells of theproximal tubule of the kidneywhere itpumps them into urine-conducting ducts, and in thecapillary endothelial cellscomposingthe blood–brain barrier andblood-testis barrier, where it pumps them back into thecapillaries.
N
N
O
Cl
H
Loperamide: Haloperidol:
N
O
Cl
OF
H
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
3.0 Methadone
ON
Methadone is a synthetic opioid, used medicallyas an analgesic, antitussive anda maintenanceanti-addictive for use in patients on opioids. Itwas developed in Germany in 1937. Methadoneis a full µ-opioid agonist. Although chemicallyunlike morphine or heroin, methadone also actson the opioid receptorsand thusproducesmany
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
(RS)-6-(Dimethylamino)-4,4-diphenylheptan-3-one
on the opioid receptorsand thusproducesmanyof the same effects. Methadone is also used inmanaging chronic pain owing to its long durationof action and very low cost.There are two methadone isomers. The racemicmixture is more common as it is cheaper toproduce.
logP = 3.9pKa = 8.9
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
Stefano Moro
Chimica e Tecnologia
Farmaceutiche
1. Pain and Narcotic Analgesics1. Pain and Narcotic Analgesics
The mechanism of action of heroin at the delta (δ) and kappa (κ) opiatereceptorsHeroinmodifies the action of dopamine in the nucleus accumbens and theventral tegemental area of the brain – these areas formpart of the brain’s‘reward pathway’. Once crossing the blood-brain barrier, heroin isconvertedto morphine, which acts as a weak agonist at the delta andkappa opioid receptorssubtypes. This binding inhibits the releaseof
Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy
kappa opioid receptorssubtypes. This binding inhibits the releaseofGABA from the nerve terminal, reducing the inhibitory effect of GABAon dopaminergic neurons. The increased activation of dopaminergicneuronsand the release of dopamine into the synaptic cleft results inactivation of the post-synaptic membrane. Continued activation of thedopaminergicreward pathway leads to the feelings of euphoria and the‘high’ associated with heroin use. Morphine is a powerful agonist at theopioid mu receptor subtype and activation of these receptors has a strongactivatingeffect on the dopaminergic reward pathway.