Gate Control Theory - Copy

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NEUROBIOLOGY NEUROBIOLOGY

of PAINof PAIN

Don PierceDon Pierce



PAINPAINPAINPAIN

µµPain is an unpleasant sensory and emotionalPain is an unpleasant sensory and emotional

experience associated with actual or potentialexperience associated with actual or potential

tissue damage, or described in terms of suchtissue damage, or described in terms of such

damage.damage.---- Pain is always subjective. EachPain is always subjective. Eachindividual learns the application of the wordindividual learns the application of the word

through experience related to injury in earlythrough experience related to injury in early

life. It is unquestionably a sensation in a partlife. It is unquestionably a sensation in a partof the body but is also always unpleasant andof the body but is also always unpleasant and

therefore also an emotional experience.¶therefore also an emotional experience.¶



PAIN¶S VARIABLE FACE







PAIN RECPTORSPAIN RECPTORSPAIN RECPTORSPAIN RECPTORS



PRIMARY AFFERENTSPRIMARY AFFERENTS

Initial inputInitial input ± ± bradykinin, histamine, bradykinin, histamine,

prostaglandin E2, cyclic adenosine prostaglandin E2, cyclic adenosine

monophosphate, thermal factors and pH.monophosphate, thermal factors and pH.

Ionic channelsIonic channels ± ± sodium and calciumsodium and calcium

mediated; multiple subtypesmediated; multiple subtypes± ± differentiallydifferentially

stimulated.stimulated.






TRANSMISIONTRANSMISION




Peripheral MessagingPeripheral Messaging

Sodium channels(v1.8, 1.9) release glutamate in the dorsalSodium channels(v1.8, 1.9) release glutamate in the dorsal

hornhorn AMPA & NMDA Glutamate also activates kianateAMPA & NMDA Glutamate also activates kianate

receptorsreceptors -- positive feedback loop positive feedback loop more glutamate.more 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 channelsCalcium mediated channels calcitonin genecalcitonin gene ± ± relatedrelated

peptide (CGRP) as well as nitric oxide (NO). Leads to peptide (CGRP) as well as nitric oxide (NO). Leads tovasodilatation, endothelial permeability & tissue swelling.vasodilatation, endothelial permeability & tissue swelling.



SENTIZATION KEY POINTSSENTIZATION KEY POINTS

All afferents become sensitized with repeatedAll afferents become sensitized with repeated

stimulationstimulation-- ³windup´ in seconds.³windup´ in seconds.

Within seconds to minutes ³sensitization´:Within seconds to minutes ³sensitization´:Mild pain stimuliMild pain stimuli hyperalgesiahyperalgesia

Innocuous stimuliInnocuous stimuli pain: pain: allodyniaallodynia

Injured CInjured C--fibers may fire spontaneouslyfibers may fire spontaneously

AA--beta fibers may send pain messages. beta fibers may send pain messages.

involves ³second messengers´ (DRGinvolves ³second messengers´ (DRG

mitochondria)mitochondria)



PAIN GATE THEORYPAIN GATE THEORY

Melzack & Wall 1965Melzack & Wall 1965

proposed a balance of input by large A proposed a balance of input by large A--beta & beta &AA--delta excitatory/excitatory and small Cdelta excitatory/excitatory and small C

fibers excitatory/inhibitory fibers.fibers excitatory/inhibitory fibers.



GATE THEORYGATE THEORY



PAIN GATE THEORYPAIN GATE THEORY

AA--delta thinly myelinated fibers provide rapiddelta thinly myelinated fibers provide rapid

response with positive input to stimulating andresponse with positive input to stimulating and

inhibiting areas in the dorsal horn.inhibiting areas in the dorsal horn.

C fibers provide slower response with postiveC fibers provide slower response with postivestimulation to activation areas and negativestimulation to activation areas and negative

input to inhibiting areas in the dorsal horn.input to inhibiting areas in the dorsal horn.

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



SPINAL AFFERENTSSPINAL AFFERENTS

Doral HornDoral Horn

GlutamateGlutamate AMPA and NMDA and activated kianateAMPA and NMDA and activated kianate

receptors providing a positive feedback loop to releasereceptors providing a positive feedback loop to release

even more glutamate and subsequently lowers thresholdeven 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 asreleases 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 ranGABA is main inhibitory transmitter; also ran -- glycineglycine



REQUIRED MEMORIZATIONREQUIRED MEMORIZATIONREQUIRED MEMORIZATIONREQUIRED MEMORIZATION





Second MessengersSecond Messengers



NEUROMEDIATORS IN THENEUROMEDIATORS IN THE

DORSAL HORNDORSAL HORN



WINDUP/SENSITIZATIONWINDUP/SENSITIZATION

NEURAL PLASTICITYNEURAL PLASTICITY

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

Actual neural growth in the Tract of Lissauer aboveActual neural growth in the Tract of Lissauer aboveand below the initial dermatome representing theand below the initial dermatome representing theinitial area of injuryinitial area of injury

protein called protein called Fos Fos -- inducible transcription f actorinducible transcription f actor

(ITF) that controls mammalian gene expression.(ITF) that controls mammalian gene expression.Central nervous system cCentral nervous system c--fos expression correlatesfos expression correlateswell with painful stimulation..well with painful stimulation..



CC--FosFos

CC--fos is a protofos is a proto--oncogeneoncogene -- promotes 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 ITFsFos 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 isApoptosis of GABAergic inhibitory neurons is

major featuremajor feature ± ± one week.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 R epresentationCortical R epresentation



Cortical R epresentationCortical R epresentation



Midbrain structuresThe peri-aqueductal grey matter (PAG)deep layers of the superior colliculus

red nucleus

pre-tectal nuclei

nucleus of Darkschewitsch

interstitial nucleus of Cajal

intercolliculus nucleus,

nucleus cuneiformis

Edinger-Westphal nucleus



MODULATIONMODULATIONMODULATIONMODULATION

sites of descending modulationsites of descending modulation--

PAG, PVG synapse in rostroventral medullaPAG, PVG synapse in rostroventral medulla

via reticulospinal tractvia reticulospinal tract -- includes theincludes the 55--HTHT producing raphae magnus producing raphae magnus to laminae I, II and V.to laminae I, II and V.

Cortex (parietal areas 1,2 &3) and diencephalonCortex (parietal areas 1,2 &3) and diencephalon

via corticospinal tractvia corticospinal tract



MODULATIONMODULATION

Descending ModulationDescending Modulation



Descending ModulationDescending Modulation

Descending modulation greatly changesDescending modulation greatly changesconcentration and activity of NMDA receptorsconcentration and activity of NMDA receptors

Descending modulation affects apoptosis of Descending modulation affects apoptosis of GABAergic inhibitoryGABAergic inhibitoryinterneurons/dysinhibitioninterneurons/dysinhibition

Descending modulation is through dynorphinsDescending modulation is through dynorphins

and change in opioid receptor number/activityand change in opioid receptor number/activitymay contribute to opioid tolerance/painmay contribute to opioid tolerance/painsensitivitysensitivity



ENDOGENOUS OPIATESENDOGENOUS OPIATES

high concentration in the spinal dorsal hornhigh concentration in the spinal dorsal hornand medullaand medulla -- also hypothalamus andalso hypothalamus and peripherally. peripherally.

Three classes:Three classes:

ßß--endorphinsendorphins-- basal hypothalamus basal hypothalamus --Proopiomelanocortin is the precursor for ßProopiomelanocortin is the precursor for ß--END,END,ACTH, and MSHACTH, and MSH

EnkephalinsEnkephalins -- dorsal horn, rahpe magnus, and thedorsal horn, rahpe magnus, and theglobus pallidusglobus pallidus -- spinal actionspinal action

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



Various Opiate ReceptorsVarious Opiate Receptors

Receptor Primary

Ligand

Other

Q Pro ENK A heroin

O Pro ENK B - DYN, pentazocine

H Pro ENK A-

ENK

I F-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 messagethereafter the transmission of the pain messageis subject to significant modulation.is subject to significant modulation.

The brain itself filters, selects, and modulatesThe brain itself filters, selects, and modulatesinputs through up & downinputs through up & down--regulation,regulation,multichannel neural as well as hormonalmultichannel neural as well as hormonalfeedback.feedback.

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



SUMMARYSUMMARY

The complexity of the feedback system limitsThe complexity of the feedback system limits

conclusions from simple analysis.conclusions from simple analysis.

In the evaluation of treatment modalities, it isIn 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 complexSince most neural circuitry involves complex

feedback loops and modulation with multiplefeedback loops and modulation with multipleneurotransmittersneurotransmitters ± ± multimulti± ± modality treatmentmodality 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.iasphttp://www.iasp--pain.org/terms pain.org/terms--p.html 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.iasphttp://www.iasp--pain.org/PCU00 pain.org/PCU00--2.html2.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: amolecular identity for nocioceptors. Current Opinion

in Neurobiology 1999, 9:525±530

9 Woolf M. Pain: Moving from Symptom Controltoward Mechanism-Specific Pharmacologic

Management. AIM 2004; 140: 441-451.

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