Gate Control Theory

NEUROBIOLOGYNEUROBIOLOGYof PAINof PAIN

Don PierceDon Pierce

PAINPAINPAINPAIN ‘‘Pain is an unpleasant sensory and emotional Pain is an unpleasant sensory and emotional

experience associated with actual or potential experience associated with actual or potential tissue damage, or described in terms of such tissue damage, or described in terms of such damage.-- Pain is always subjective. Each damage.-- Pain is always subjective. Each individual learns the application of the word individual learns the application of the word through experience related to injury in early through experience related to injury in early life. It is unquestionably a sensation in a part life. It is unquestionably a sensation in a part of the body but is also always unpleasant and of the body but is also always unpleasant and therefore also an emotional experience.’ therefore also an emotional experience.’

PAIN’S VARIABLE FACE

PAIN’S VARIABLE FACE

PAIN’S VARIABLE FACE

PAIN RECPTORSPAIN RECPTORSPAIN RECPTORSPAIN RECPTORS

PRIMARY AFFERENTSPRIMARY AFFERENTS

Initial input – bradykinin, histamine, Initial input – bradykinin, histamine, prostaglandin E2, cyclic adenosine prostaglandin E2, cyclic adenosine monophosphate, thermal factors and pH.monophosphate, thermal factors and pH.

Ionic channels – sodium and calcium Ionic channels – sodium and calcium mediated; multiple subtypes– differentially mediated; multiple subtypes– differentially stimulated.stimulated.

PRIMARY AFFERENTSPRIMARY AFFERENTS

TRANSMISIONTRANSMISION

PRIMARY AFFERENTSPRIMARY AFFERENTS Peripheral MessagingPeripheral Messaging

Sodium channels(v1.8, 1.9) release glutamate in the dorsal Sodium channels(v1.8, 1.9) release glutamate in the dorsal horn horn AMPA & NMDA Glutamate also activates AMPA & NMDA Glutamate also activates kianate receptors - positive feedback loop kianate receptors - positive feedback loop more more glutamate.glutamate.

Calcium mediated channels (thermal/pH ,C fiber type) Calcium mediated channels (thermal/pH ,C fiber type) substance P. substance P. NMDA NMDA positive peripheral nocioceptor positive peripheral nocioceptor recruitment.recruitment.

Calcium mediated channels Calcium mediated channels calcitonin gene – related calcitonin gene – related peptide (CGRP) as well as nitric oxide (NO). Leads to peptide (CGRP) as well as nitric oxide (NO). Leads to vasodilatation, endothelial permeability & tissue swelling.vasodilatation, endothelial permeability & tissue swelling.

SENTIZATION KEY POINTSSENTIZATION KEY POINTS

All afferents become sensitized with repeated All afferents become sensitized with repeated stimulation- “windup” in seconds.stimulation- “windup” in seconds.

Within seconds to minutes “sensitization”:Within seconds to minutes “sensitization”: Mild pain stimuli Mild pain stimuli hyperalgesiahyperalgesia Innocuous stimuli Innocuous stimuli pain: pain: allodyniaallodynia Injured C-fibers may fire spontaneouslyInjured C-fibers may fire spontaneously A-beta fibers may send pain messages.A-beta fibers may send pain messages. involves “second messengers” (DRG involves “second messengers” (DRG

mitochondria)mitochondria)

PAIN GATE THEORYPAIN GATE THEORY

Melzack & Wall 1965Melzack & Wall 1965 proposed a balance of input by large A-beta & proposed a balance of input by large A-beta &

A-delta excitatory/excitatory and small C A-delta excitatory/excitatory and small C fibers excitatory/inhibitory fibers.fibers excitatory/inhibitory fibers.

GATE THEORYGATE THEORY

PAIN GATE THEORYPAIN GATE THEORY A-delta thinly myelinated fibers provide rapid A-delta thinly myelinated fibers provide rapid

response with positive input to stimulating and response with positive input to stimulating and inhibiting areas in the dorsal horn. inhibiting areas in the dorsal horn.

C fibers provide slower response with postive C fibers provide slower response with postive stimulation to activation areas and negative stimulation to activation areas and negative input to inhibiting areas in the dorsal horn.input to inhibiting areas in the dorsal horn.

A-beta are recruited after repeated stimulation.A-beta are recruited after repeated stimulation.

SPINAL AFFERENTSSPINAL AFFERENTS Doral HornDoral Horn

Glutamate Glutamate AMPA and NMDA and activated kianate AMPA and NMDA and activated kianate receptors providing a positive feedback loop to release receptors providing a positive feedback loop to release even more glutamate and subsequently lowers threshold even more glutamate and subsequently lowers threshold and recruits.and recruits.

Calcium mediated channels (thermal/pH ,C fiber type) Calcium mediated channels (thermal/pH ,C fiber type) releases substance P. Substance P + NMDA serves as releases substance P. Substance P + NMDA serves as positive recruitment in the tract of Lissaeur (ipsilateral) and positive recruitment in the tract of Lissaeur (ipsilateral) and (ipsilateral and contralateral) spinothalamic tracts.(ipsilateral and contralateral) spinothalamic tracts.

GABA is main inhibitory transmitter; also ran - glycineGABA is main inhibitory transmitter; also ran - glycine

REQUIRED MEMORIZATIONREQUIRED MEMORIZATIONREQUIRED MEMORIZATIONREQUIRED MEMORIZATION

Second MessengersSecond Messengers

NEUROMEDIATORS IN THE NEUROMEDIATORS IN THE DORSAL HORNDORSAL HORN

WINDUP/SENSITIZATION WINDUP/SENSITIZATION NEURAL PLASTICITYNEURAL PLASTICITY

The region of hypersensitivity progressively enlarges The region of hypersensitivity progressively enlarges beyond the initial area of injurybeyond the initial area of injury

Actual neural growth in the Tract of Lissauer above Actual neural growth in the Tract of Lissauer above and below the initial dermatome representing the and below the initial dermatome representing the initial area of injuryinitial area of injury

protein called protein called Fos - Fos - inducible transcription factorinducible transcription factor (ITF) that controls mammalian gene expression. (ITF) that controls mammalian gene expression. Central nervous system c-fos expression correlates Central nervous system c-fos expression correlates well with painful stimulation.. well with painful stimulation..

C-FosC-Fos

C-fos is a proto-oncogene - promotes C-fos is a proto-oncogene - promotes intracellular changes including cellular intracellular changes including cellular restructuring & protein proliferation.restructuring & protein proliferation.

Noxious peripheral stimulation not only causes Noxious peripheral stimulation not only causes Fos to appear in the spinal cord, but also the ITFs Fos to appear in the spinal cord, but also the ITFs -Jun and Krox and many others.-Jun and Krox and many others.

Apoptosis of GABAergic inhibitory neurons is Apoptosis of GABAergic inhibitory neurons is major feature – one week. major feature – one week.

SPINOTHALAMIC TRACTSSPINOTHALAMIC TRACTS

neospinothalamic tract for acute pain to midbrain, -VPL thalmus postcentral gyrus

paleospinothalamic tract for dull and burning pain to the reticular formation, limbic system & midbrain VM thalmus anterior cingulate gyrus

Ascending Pathways

Cortical RepresentationCortical Representation

Cortical RepresentationCortical Representation

Midbrain structuresThe peri-aqueductal grey matter (PAG)

deep layers of the superior colliculus red nucleus

pre-tectal nucleinucleus of Darkschewitsch interstitial nucleus of Cajal

intercolliculus nucleus,nucleus cuneiformis

Edinger-Westphal nucleus

MODULATIONMODULATIONMODULATIONMODULATION

sites of descending modulation-sites of descending modulation- PAG, PVG synapse in rostroventral medulla PAG, PVG synapse in rostroventral medulla

via reticulospinal tract - includes the via reticulospinal tract - includes the 5-HT 5-HT producing raphae magnusproducing raphae magnus to laminae I, II and V. to laminae I, II and V.

Cortex (parietal areas 1,2 &3) and diencephalon Cortex (parietal areas 1,2 &3) and diencephalon via corticospinal tractvia corticospinal tract

MODULATIONMODULATIONDescending ModulationDescending Modulation

Descending ModulationDescending Modulation

Descending modulation greatly changes Descending modulation greatly changes concentration and activity of NMDA receptorsconcentration and activity of NMDA receptors

Descending modulation affects apoptosis of Descending modulation affects apoptosis of GABAergic inhibitory GABAergic inhibitory interneurons/dysinhibitioninterneurons/dysinhibition

Descending modulation is through dynorphins Descending modulation is through dynorphins and change in opioid receptor number/activity and change in opioid receptor number/activity may contribute to opioid tolerance/pain may contribute to opioid tolerance/pain sensitivitysensitivity

ENDOGENOUS OPIATESENDOGENOUS OPIATES high concentration in the spinal dorsal horn high concentration in the spinal dorsal horn

and medulla - also hypothalamus and and medulla - also hypothalamus and peripherally.peripherally.

Three classes: Three classes: ß-endorphins- basal hypothalamus -ß-endorphins- basal hypothalamus -

Proopiomelanocortin is the precursor for ß-END, Proopiomelanocortin is the precursor for ß-END, ACTH, and MSHACTH, and MSH

Enkephalins - dorsal horn, rahpe magnus, and the Enkephalins - dorsal horn, rahpe magnus, and the globus pallidus - spinal actionglobus pallidus - spinal action

Dynorphins - hypothalamus, PAG, reticular Dynorphins - hypothalamus, PAG, reticular formation, and DHformation, and DH

Various Opiate ReceptorsVarious Opiate Receptors

Receptor Primary Ligand

Other

Pro ENK A heroin

Pro ENK B - DYN, pentazocine

Pro ENK A -

ENK

-Endorphin

Each has subtypes & local metabolism / sensitivity may vary

SUMMARYSUMMARY

At the peripheral receptor and every synapse, At the peripheral receptor and every synapse, thereafter the transmission of the pain message thereafter the transmission of the pain message is subject to significant modulation. is subject to significant modulation.

The brain itself filters, selects, and modulates The brain itself filters, selects, and modulates inputs through up & down-regulation, inputs through up & down-regulation, multichannel neural as well as hormonal multichannel neural as well as hormonal feedback.feedback.

Outcome may permanent and may/may not be Outcome may permanent and may/may not be beneficial to the individual.beneficial to the individual.

SUMMARYSUMMARY The complexity of the feedback system limits The complexity of the feedback system limits

conclusions from simple analysis.conclusions from simple analysis. In the evaluation of treatment modalities, it is In the evaluation of treatment modalities, it is

usual for empirical fact to be supported, rather usual for empirical fact to be supported, rather than revealed by physiologic studies.than revealed by physiologic studies.

Since most neural circuitry involves complex Since most neural circuitry involves complex feedback loops and modulation with multiple feedback loops and modulation with multiple neurotransmitters – multi– modality treatment neurotransmitters – multi– modality treatment is likely to be the most beneficial.is likely to be the most beneficial.

1 Melzack R, Wall PD. Pain mechanisms: A new theory. Science 1965;150:971–9.

2 International Association for the Study of Pain2 International Association for the Study of Pain http://www.iasp-pain.org/terms-p.htmlhttp://www.iasp-pain.org/terms-p.html

3 Molecular Biology of Pain: Should Clinicians Care? 3 Molecular Biology of Pain: Should Clinicians Care? in Pain Clinical Updatesin Pain Clinical Updates http://www.iasp-pain.org/PCU00-2.htmlhttp://www.iasp-pain.org/PCU00-2.html

4 Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:1765–9.

5 Wilcox GL. Excitatory neurotransmitters and pain. In: Bond MR, Charlton JE, Woolf CJ, eds. Proceedings of the VIth World Congress on Pain. Amsterdam, 1991. p. 97–117.

6 Rang HP, Bevan S, Dray A. Chemical activation of nociceptive peripheral neurones. Br Med Bull 1991;47:534–8. 1992;77:439–46.

7 Dubner R, Ren K. Endogenous mechanisms of sensory modulation. Pain 1999; Supplement 6:S45–S53.

8 Caterina M, Julius D. Sense and specificity: a molecular identity for nocioceptors. Current Opinion in Neurobiology 1999, 9:525–530

9 Woolf M. Pain: Moving from Symptom Control toward Mechanism-Specific Pharmacologic Management. AIM 2004; 140: 441-451.