pain processes slides

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http://www.georgiapainphysicians.com/l2_edu_pharma_mod1_slides.htm

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	Stimuli Nociceptive terminals of primary sensory neurons are stimulated by noxious stimuli 2,4
	Impulse Transmission Action potentials are generated 2
	Sensory Fibers Action potentials pass along Ad- and C-type peripheral afferent sensory fibers 2,4
	Cord Junctions Action potentials arrive at junctions between the peripheral afferent sensory fibers and spinal cord neurons 2,3,4
	Dorsal Horn Junctions between the peripheral afferent sensory fibers and spinal cord neurons are shown within the dorsal horn 3,4
	Synapse Arrival of the action potentials causes voltage-gated calcium channels to open in the terminals of the peripheral afferent sensory fibers 1,2
	Calcium Release Opening of the channels enables the influx of calcium into the peripheral afferent sensory fiber terminals, which causes vesicles containing neurotransmitter molecules to fuse with the pre-synaptic membrane and release their contents into the synaptic cleft 1
	Synaptic Cleft Neurotransmitter molecules (e.g. glutamate, substance P) diffuse across the synaptic cleft 1,2,3,4 Neurotransmitters bind to receptors on ion channels in the post-synaptic membrane 1,4
	Post Synaptic Cell Activation of receptors in the post-synaptic membrane, either via G-protein coupled effector enzymes, or directly via ion channels, enables the efflux of potassium and influx of calcium and sodium into the post-synaptic cell 1,4
	Nociceptive Nueron The influx of sodium enables the continuation of action potentials from the peripheral afferent sensory fibers, and the transmission of impulses along the axons of the spinal cord neurons to the brain 1,4
	Pain Perception Information about pain is received and processed by the higher centers in the brain (thalamus, cerebral cortex) and the individual perceives pain 2
	Opioid Receptors Areas of the spinal cord and brain are shown where the sensations of pain and the affective and psychological aspects of pain are perceived. These include the substantia gelatinosa, periaqueductal gray, reticular formation, parabrachial nucleus, hypothalamus, thalamus, cingulate cortex, and cortex 2, 5,6,7,8. Regions of the spinal cord and brain where µ-type opioid receptors are found include the substantia gelatinosa, periaqueductal gray, reticular formation, hypothalamus, thalamus, and cortex 5,6,7,8. These regions show considerable overlap with the regions that enable the perception of pain. Regions where pain is perceived are shown in brown; regions where opioid receptors are found are shown in blue. To reduce the level of perceived pain, endogenous opioids (enkephalins, dynorphin) are released by interneurons in the dorsal horn in response to severe/persistent pain. The opioids bind to G proteins associated with µ-type opioid receptors, with the following results: Inhibition of pre-synaptic release of glutamate Increased potassium conductance across the post-synaptic membrane. These events prevent the transmission of pain to the higher centers 2,4,5,6 To combat severe or persistent nociceptive or neuropathic pain, administration of exogenous opioids (e.g. morphine) mimics the effects of endogenous opioids at the µ opioid receptor resulting in blockade of the pain response 2,5.

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.

Click on photo for an enlarged version (hit "Back" button to return to this page). References listed below.

View Module 1

	Sequence 1: Tissue injury Injury Tissue injury occurs
	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
	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
	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
	Central sensitization Central sensitization results and the individual perceives greater and more prolonged pain 1,2,3.
	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
	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
	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
	Perception in higher centers Allodynia and hyperalgesia result in greater perception of pain in the higher centers 1,3.
	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
	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
	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.
	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
	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
	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.
	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
	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
	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
	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
	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.

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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