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This
page contains Module 2 of Purdue Pharma LP's Pain.
This module focuses on more advanced pathphysiological processes and
nociceptive and nueropathic pain responses.
©
2002 Purdue Pharma L.P. Any unauthorized reproduction of these
materials is strictly prohibited. If you are interested in obtaining
permission to use this media, contact Purdue Pharma L.P.'s Medical
Education Department at 203-588-8000.
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on photo for an enlarged version (hit "Back" button to return to
this page). References listed below.
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Module 1
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Sequence 1: Tissue injury
Injury
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Pain inflammatory mediators
- Tissue injury causes the release of various
inflammatory and pain mediators resulting in peripheral
sensitization 1,2,3
- Pain response mediators: ATP, acetylcholine and
serotonin are released from damaged endothelial cells and
platelets; prostaglandin E2 is synthesized by Cyclooxygenase
I and II enzymes in damaged cells; bradykinin is released
from plasma from damaged vessels
1,2
- Inflammatory response mediators: Histamine is
released from mast cells in response to Substance P and
calcitonin gene-related peptide (CGRP) released by primary
afferent sensory fibers; additional mediators are released
from blood cells (cytokines, complement factors C3a and C5a,
serotonin, platelet-activating factor, neutrophil
chemotactic factor, fibrinopeptides, leukotrienes) 1,2
- Together with bradykinin and prostaglandins, these
inflammatory mediators cause peripheral vasodilation,
increased vascular permeability, plasma extravasation,
migration of leucocytes to the site of injury, and clotting
responses 1
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Peripheral senstization
- Bradykinin stimulates further synthesis/release of
prostaglandins, and, together with the prostaglandins,
sensitizes the primary afferent sensory fibers in response
to stimulation by ATP, acetylcholine, serotonin and
mechanical and thermal stimuli 1,2,3
- Substance P and CGRP released by the primary afferent
sensory fibers contribute to the pain response by triggering
the release of histamine from mast cells which, in turn,
excites the peripheral afferent sensory fibers 1,2,3
- " Sensitization of the primary afferent sensory
fibers by mediators of the pain response results in greater,
more frequent transmission of action potentials to the
nociceptive neurons than in 'normal' pain responses 1,2,5
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Hyperexitation
- At the synapse level, sensitized primary afferent
sensory fibers decrease the threshold for activation of
nociceptor neurons which become hyperexcitable and transmit
frequent action potentials 1,2
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Central sensitization
- Central sensitization results and the individual
perceives greater and more prolonged pain 1,2,3.
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Sequence 2: Nociceptive pain
Allodynia
- Tissue injury often results in nociceptive pain, in
which persistent pain is felt in response to direct
activation of peripheral nerve terminals in the skin by pain
response mediators from the damaged tissue 1,2
- Nociceptive pain: Following tissue injury, Substance
P, CGRP and glutamate are released by peripheral afferent
sensory fibers and act on peptide and glutamate receptors on
the post-synaptic membrane to cause greater excitability of
nociceptive neurons. Nociceptive neurons become
hyperexcitable, resulting in central sensitization and thus
greater perception of pain in the higher centers 1,2,3
- Nociceptive pain may involve the abnormal pain states
of allodynia or hyperalgesia which result from both
peripheral and central hypersensitivity 1,2,3
- Allodynia: Certain types of noxious stimulus (e.g.
sunburn, injury, post-surgical wounds) may result in the
individual perceiving pain in response to stimuli that are
not normally painful, such as a light stroking of the
skin 1,2,4
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Hyperalgesia
- Hyperalgesia: Certain noxious stimuli (e.g. severe
bruising) can result in the individual perceiving abnormally
high levels of pain in response to normal noxious stimuli
such as a small scratch; in such cases, patients often
perceive spontaneous pain 1,2,4
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Greater transmission of AP's
- Allodynia and hyperalgesia result in greater and
continued transmission of action potentials along the
peripheral afferent sensory fibers 1,3
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Perception in higher centers
- Allodynia and hyperalgesia result in greater
perception of pain in the higher centers 1,3.
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Sequence 3: Nueropathic Pain
Partial Nerve Severance
- Neuropathic pain occurs following direct injury to
the nerves in the peripheral or central nervous systems.
Neuropathic pain can result from complete or partial nerve
transection, nerve compression, infiltration or
infectious/inflammatory/ischemic etiologies 1,2,4
- Partial severance of peripheral afferent sensory
fibers results in neuropathic pain in the form of ectopic
activity4
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Ectopic Activity
- Ectopic activity: Nerve damage results in the
accumulation of sodium channels 2,5
- The accumulation of sodium channels generates action
potentials in the damaged peripheral afferent sensory fibers
proximal to the injury site 2,5
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Hyperexitability
- The focus of excitability in the damaged sensory
fibers causes the stimulation of the higher centers to
perceive spontaneous pain (e.g. phantom pain, sciatica)
2,4,5.
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Sequence 4: Nueropathic pain:
Ephaptic
Ephaptic activity
- In addition to ectopic activity, direct nerve injury
can cause a different form of neuropathic pain due to
ephaptic activity 4
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Cross talk
- Ephaptic transmission: Complete severance of
peripheral afferent sensory fibers results in
hyperexcitability of damaged nerves and transmission of
action potentials along adjacent, undamaged unstimulated
sensory fibers, or cross talk 4
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Receptive field expands
- Cross-talk between damaged, stimulated peripheral
afferent sensory fibers and adjacent unstimulated fibers
results in an expansion of the area in which pain is
perceived in and around the area of the damaged nerve 4.
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Section 5: Wind up
Tissue injury/nerve damage
- Both the tissue injury and nerve damage responsible
for severe/persistent nociceptive and neuropathic pain can
result in a process termed wind-up
1,3,4
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Repeated firing of PAF's
- During wind up, the peripheral afferent sensory
fibers fire repeatedly, there is increased transmitter
release into the spinal cord, and the response by spinal
cord neurons increases progressively 1,3,4
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Ion channels
- In the synapse, repeated firing from peripheral
afferent sensory fibers and consequent release of glutamate
results in the prolonged opening of post-synaptic ion
channels gated by N-methyl-D-aspartate (NMDA)-type glutamate
receptors 1,2,3
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Wind up
- Prolonged opening of the ion channels enables greater
influx of calcium and sodium across the post-synaptic
membrane and greater excitation of nociceptive neurons 2,3
- Wind-up causes long-term changes in nociceptive
neurons, which become hyperexcitable such that they respond
to lower stimuli; central sensitization results. NMDA-type
glutamate receptors play an important role in this process
1,2,3,4
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Receptive field expands
- The hyperexcitability resulting from wind-up causes a
higher perception of pain, such that weak stimuli cause
pain, spontaneous pain may be perceived, and the receptive
field expands 1,2,4.
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References:
1.
Kandel ER, Schwartz JH, Jessell TM, editors. Principles of Neural
Science (Fourth Edition). New York: McGraw Hill (Health Professions
Division). 2000;472-491.
2.
Millan MJ. Progress in Neurobiology 1999;57:1-164.
3.
Dickenson AH. Brit J Anaesthesia 1995;75:193-200.
4.
Suzuki R and Dickenson AH. Neuroreport 2000;11:R17-21.
5.
Waxman S. Pain 1999;6:S133-140.
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