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NEUROBIOLOGY

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

PAIN’S VARIABLE FACE


PAIN RECPTORS
PRIMARY AFFERENTS
 Initial input – bradykinin, histamine,
prostaglandin E2, cyclic adenosine
monophosphate, thermal factors and pH.

 Ionic channels – sodium and calcium


mediated; multiple subtypes– differentially
stimulated.
PRIMARY AFFERENTS
TRANSMISION
PRIMARY AFFERENTS
 Peripheral Messaging
 Sodium channels(v1.8, 1.9) release glutamate in the dorsal
horn  AMPA & NMDA Glutamate also activates
kianate receptors - positive feedback loop  more
glutamate.
 Calcium mediated channels (thermal/pH ,C fiber type) 
substance P.  NMDA  positive peripheral nocioceptor
recruitment.
 Calcium mediated channels calcitonin gene – related
peptide (CGRP) as well as nitric oxide (NO). Leads to
vasodilatation, endothelial permeability & tissue swelling.
SENTIZATION KEY POINTS
 All afferents become sensitized with repeated
stimulation- “windup” in seconds.
 Within seconds to minutes “sensitization”:
 Mild pain stimuli hyperalgesia
 Innocuous stimuli pain: allodynia
 Injured C-fibers may fire spontaneously
 A-beta fibers may send pain messages.
 involves “second messengers” (DRG
mitochondria)
PAIN GATE THEORY

Melzack & Wall 1965


 proposed a balance of input by large A-beta &

A-delta excitatory/excitatory and small C


fibers excitatory/inhibitory fibers.
GATE THEORY
PAIN GATE THEORY
 A-delta thinly myelinated fibers provide rapid
response with positive input to stimulating and
inhibiting areas in the dorsal horn.
 C fibers provide slower response with postive
stimulation to activation areas and negative
input to inhibiting areas in the dorsal horn.
 A-beta are recruited after repeated stimulation.
SPINAL AFFERENTS
 Doral Horn
 Glutamate  AMPA and NMDA and activated kianate
receptors providing a positive feedback loop to release
even more glutamate and subsequently lowers threshold
and recruits.
 Calcium mediated channels (thermal/pH ,C fiber type)
releases substance P. Substance P + NMDA serves as
positive recruitment in the tract of Lissaeur (ipsilateral) and
(ipsilateral and contralateral) spinothalamic tracts.
 GABA is main inhibitory transmitter; also ran - glycine
REQUIRED MEMORIZATION
Second Messengers
NEUROMEDIATORS IN THE
DORSAL HORN
WINDUP/SENSITIZATION
NEURAL PLASTICITY
 The region of hypersensitivity progressively enlarges
beyond the initial area of injury
 Actual neural growth in the Tract of Lissauer above
and below the initial dermatome representing the
initial area of injury
 protein called Fos - inducible transcription factor
(ITF) that controls mammalian gene expression.
Central nervous system c-fos expression correlates
well with painful stimulation..
C-Fos
 C-fos is a proto-oncogene - promotes
intracellular changes including cellular
restructuring & protein proliferation.
 Noxious peripheral stimulation not only causes
Fos to appear in the spinal cord, but also the ITFs
-Jun and Krox and many others.
 Apoptosis of GABAergic inhibitory neurons is
major feature – one week.
Ascending Pathways
SPINOTHALAMIC 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
Cortical Representation
Cortical Representation
Midbrain structures
The 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
MODULATION
 sites of descending modulation-
 PAG, PVG synapse in rostroventral medulla
via reticulospinal tract - includes the 5-HT
producing raphae magnus to laminae I, II and V.
 Cortex (parietal areas 1,2 &3) and diencephalon

via corticospinal tract


Descending Modulation
MODULATION
Descending Modulation
 Descending modulation greatly changes
concentration and activity of NMDA receptors
 Descending modulation affects apoptosis of
GABAergic inhibitory
interneurons/dysinhibition
 Descending modulation is through dynorphins
and change in opioid receptor number/activity
may contribute to opioid tolerance/pain
sensitivity
ENDOGENOUS OPIATES
 high concentration in the spinal dorsal horn
and medulla - also hypothalamus and
peripherally.
 Three classes:
 ß-endorphins- basal hypothalamus
-Proopiomelanocortin is the precursor for ß-END,
ACTH, and MSH
 Enkephalins - dorsal horn, rahpe magnus, and the
globus pallidus - spinal action
 Dynorphins - hypothalamus, PAG, reticular
formation, and DH
Various Opiate Receptors
Receptor Primary Other
Ligand
 Pro ENK A heroin

 Pro ENK B - DYN, pentazocine

 Pro ENK A ENK


-
 -Endorphin

Each has subtypes & local metabolism / sensitivity may vary


SUMMARY
 At the peripheral receptor and every synapse,
thereafter the transmission of the pain message
is subject to significant modulation.
 The brain itself filters, selects, and modulates
inputs through up & down-regulation,
multichannel neural as well as hormonal
feedback.
 Outcome may permanent and may/may not be
beneficial to the individual.
SUMMARY
 The complexity of the feedback system limits
conclusions from simple analysis.
 In the evaluation of treatment modalities, it is
usual for empirical fact to be supported, rather
than revealed by physiologic studies.
 Since most neural circuitry involves complex
feedback loops and modulation with multiple
neurotransmitters – multi– modality treatment
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 Pain
 http://www.iasp-pain.org/terms-p.html
3 Molecular Biology of Pain: Should Clinicians Care?
in Pain Clinical Updates
 http://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.

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