Update on the Neurophysiology of Pain Transmission and Modulation: Focus on the NMDA-Receptor
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1 S2 Journal of Pain and Symptom Management Vol. 19 No. 1(Suppl.) January 2000 Proceedings Supplement NMDA-Receptor Antagonists: Evolving Role in Analgesia Update on the Neurophysiology of Pain Transmission and Modulation: Focus on the NMDA-Receptor Gary J. Bennett, PhD Department of Neurology, MCP Hahnemann University, Philadelphia, Pennsylvania, USA Abstract Pain is detected by two different types of peripheral nociceptor neurons, C-fiber nociceptors with slowly conducting unmyelinated axons, and A-delta nociceptors with thinly myelinated axons. During inflammation, nociceptors become sensitized, discharge spontaneously, and produce ongoing pain. Prolonged firing of C-fiber nociceptors causes release of glutamate which acts on N-methyl-D-aspartate (NMDA) receptors in the spinal cord. Activation of NMDA receptors causes the spinal cord neuron to become more responsive to all of its inputs, resulting in central sensitization. NMDA-receptor antagonists, such as dextromethorphan, can suppress central sensitization in experimental animals. NMDA-receptor activation not only increases the cell s response to pain stimuli, it also decreases neuronal sensitivity to opioid receptor agonists. In addition to preventing central sensitization, co-administration of NMDA-receptor antagonists with an opioid may prevent tolerance to opioid analgesia. J Pain Symptom Manage 2000;19:S2 S6. U.S. Cancer Pain Relief Committee, Key Words NMDA-receptor antagonists, pain transmission, opioid tolerance, central sensitization, allodynia, hyperalgesia, neuropathy Introduction For many years, the neurophysiological analysis of pain transmission focused on responses evoked by an acute noxious stimulus, e.g., a pinprick or a few seconds exposure to painful heat. It was realized that clinically significant pain might be very different, but the hope was that it would be different in degree, not in kind. We now know that this is not true chronic pain caused by inflammation or nerve Address reprint requests to: Gary J. Bennett, PhD, Department of Neurology, MCP Hahnemann University, Broad and Vine Streets, Philadelphia, PA Accepted for publication: September 17, injury (neuropathic pain) is due, at least in part, to unique mechanisms in the peripheral and central nervous system. 1 Peripheral Nervous System The skin, muscle and tendon, periosteum and synovium, heart and blood vessels, and the viscera (or the connective tissues capsules that encase them) are all innervated by somatosensory primary afferent neurons that are specialized to respond to stimuli that cause, or threaten to cause, tissue injury. These painsensing afferent neurons, called nociceptors, come in two general types, one with slowly conducting unmyelinated axons (C-fiber nociceptors) and the other with thinly myeli- U.S. Cancer Pain Relief Committee, /00/$ see front matter Published by Elsevier, New York, New York PII S (99)
2 Vol. 19 No. 1(Suppl.) January 2000 NMDA-Receptors and Pain Transmission S3 nated axons (A-delta nociceptors). In normal tissue they are silent in the absence of tissue injury; when injury occurs, their rate of discharge increases as a function of the amount of tissue damage, i.e., nociceptors signal the occurrence of pain and encode its intensity. In the presence of inflammation, nociceptors acquire new characteristics and are said to be sensitized: (1) They begin to discharge spontaneously. This spontaneous, or ongoing, discharge is at least partly responsible for the ongoing pain (soreness) that follows a tissue injury. (2) Their threshold for activation is decreased such that normally innocuous stimuli now cause pain (e.g., the pain felt when lightly touching a burn; a phenomenon called allodynia). (3) Their stimulus response curves are shifted to the left, such that a noxious stimulus causes more pain than normal, a condition called hyperalgesia (e.g., the pain of being slapped on a sunburnt back). The decrease in threshold and the leftward shift of the stimulus response function underlie the tenderness of an injured region and its immediate surround. Sensitized nociceptors also acquire an excitatory response to norepinephrine; thus, there is a link between pain and sympathetic nervous system discharge. 2,3 In the case of neuropathic pain, nociceptors also change their characteristics. If their axon has been interrupted, the regenerating sprout may discharge spontaneously and become extremely sensitive to mechanical, thermal, and ionic stimulation. Similar, but less pronounced, changes are seen in nociceptors that escape injury themselves but travel in the vicinity of damaged axons. 4 6 Central Nervous System Spontaneously discharging nociceptors will give rise to ongoing pain. Unfortunately, that is not all. Unmyelinated (C-fiber) nociceptors release glutamate as their neurotransmitter. The spinal cord neurons that receive input from C-nociceptors express three subtypes of glutaminergic receptor: the N-methyl-D-aspartate (NMDA) subtype, the kainate/ampa (l-amino- 3-hydroxy-5-methylsoxasole-propionic acid) subtype, and the metabotropic subtype. Glutamate released from C-nociceptors and acting at NMDA receptors evokes a change in the sensitivity of the postsynaptic cell such that it responds more strongly to all of its inputs (Figure 1), an effect called central sensitization. Very recent data suggest that something simi- Fig. 1. An experiment showing the effects of NMDA-receptor antagonists on central sensitization. Following decerebration and spinalization under general anesthesia, rats were prepared for the electrophysiological recording of the discharges of flexor motoneurons innervating the thigh. Flexor motoneuron discharges were evoked by a standardized painful pinch to the toes every 5 minutes. The motoneuron discharge causes the pain withdrawal reflex; in humans, the magnitude of the reflex corresponds to the magnitude of pain perceived. Prior to painting the skin with mustard oil (MO), each pinch evokes a fairly constant baseline pain withdrawal reflex. Mustard oil, a vesicant that selectively excites C-nociceptors, causes an intense burning pain sensation of about 1 minute duration. Following the pain input caused by MO, the reflex is greatly enlarged for over an hour. The increased reflex, and the increased perceived pain that would accompany it, indicate the presence of central sensitization. Pretreatment (left-hand graph) with NMDA antagonists (CPP or MK-801) prevents central sensitization, whereas posttreatment (right-hand graph) reverses it. Reproduced with permission from Woolf and Thompson. 7
3 S4 Bennett Vol. 19 No. 1(Suppl.) January 2000 lar may also be happening via glutamate activation of kainate/ampa channels, but most of the data in hand implicates the NMDA receptor. Activation of the NMDA receptor causes the spinal cord neuron to become more responsive to all of its inputs, including input from damaged or sensitized nociceptors and input from low-threshold mechanoreceptors ( touch fibers). It is important to note that central sensitization is evoked by any kind of C-nociceptor input. 8 Normal input from uninjured tissue produces a small and fleeting amount of central sensitization, but the large and prolonged input from C-nociceptors that are sensitized as a consequence of tissue inflammation, or that discharge spontaneously because of nerve injury, can produce prominent and long-lasting central sensitization. Central sensitization has been demonstrated in animals, even in the presence of a surgical level of general anesthetic. It can be demonstrated also in the normal human volunteer. For example, an intradermal injection of capsaicin (the active ingredient in chili peppers and a specific stimulant for C-nociceptors) produces a very strong burning pain sensation that lasts for about 20 minutes. After the injection pain has waned (and even before that), the skin surrounding the injection site becomes allodynic and hyperalgesic for hours (Figure 2). The allodynia and hyperalgesia can be reversed by NMDA-receptor blockade is an antitussive that has been on the market for many years and has established an excellent safety record. Memantine also has been shown in European studies to be well-tolerated in elderly patients to retard the progression of Alzheimer s disease. Clinical experience indicates that neuropathic pain is relatively (in some cases almost completely) resistant to opiate analgesics. Data from experiments on diverse topics show that this is due to an interaction between the intracellular events that mediate central sensitization and those that regulate the sensitivity of the mu subtype of opiate receptor. Pain-evoked NMDA-receptor activation increases the cell s responses to its stimuli, while it also decreases the efficacy of mu-receptor agonists. Thus, a patient with neuropathic hyperalgesia has a sort of pain-evoked opiate tolerance, even in NMDA-Receptor Antagonists There is universal agreement that NMDAreceptor antagonists of diverse chemistry suppress central sensitization in experimental animals (Table 1), and there are several demonstrations of efficacy in humans NMDA-receptor blockers that have been shown to be effective include some familiar drugs that happen to have NMDA antagonist properties, e.g., dextromethorphan, dextrorphan, memantine, ketamine, and amantadine. The clinical usefulness of some of these drugs is limited by a very narrow therapeutic index due to unacceptable effects on mental functioning. Ketamine, for example, has demonstrable efficacy as an NMDAreceptor antagonist, but its psychotomimetic effects will probably preclude its use in the clinic. On the other hand, dextromethorphan Fig. 2. Central sensitization demonstrated in a normal human volunteer. An intradermal injection of 100 g of capsaicin (in a volume of 10 l) is made on the volar forearm. Ten to 20 minutes of intense burning pain follows the injection. Thereafter the skin surrounding the injection site is allodynic and hyperalgesic. Stroking the skin with a cotton swab evokes a burning pain sensation. Poking (not penetrating) the skin with a pin (punctate) evokes a strong, stinging, electric shock-like pain that far exceeds the normal, barely painful sensation evoked by pin prick. The injection raises a bleb that becomes analgesic (C-nociceptors fall silent and are not excitable after discharging strongly to the capsaicin). A small region surrounding the bleb becomes hypersensitive to heat stimuli. A prominent flare response is evoked in an area surrounding the bleb. Note that the allodynic and hyperalgesic response to stroking and punctate stimuli must be mediated via a change in CNS processing because the capsaicin does not diffuse from the injection site. Reproduced with permission from LaMotte et al. 9
4 Vol. 19 No. 1(Suppl.) January 2000 NMDA-Receptors and Pain Transmission S5 Table 1 Effects of Diverse NMDA-Receptor Blockers on Neuropathic Pain Seen in Experimental Models of Painful Peripheral Neuropathy in the Rat Drug Model Route Test Ref. MK-801 CCI 13 i.p. heat Davar et al. 14 CCI i.t. heat Yamamoto and Yaksh 15 CCI i.t. heat, spon Mao et al. 16 K & C 17 i.t. M-allo Chaplan et al. 18 AP-5 CCI i.t. Heat Yamamoto and Yaksh 15 K & C i.t. M-allo Chaplan et al. Ketamine CCI i.t. Heat Yamamoto and Yaksh 15 CCI i.t. heat, spon Mao et al. 16 Dextromethorphan, dextrorphan CCI i.p., i.t. heat Tal and Bennett 19 CCI i.t. heat Mao et al. 20 K & C i.t. M-allo Chaplan et al. 18 Memantine CCI i.p. heat Eisenberg et al. 21 CCI i.p. heat Chaplan et al. 18 Mg CCI i.t. heat Xiao and Bennett 22 CCI the chronic constriction model of Bennett and Xie 13 ; K&C the spinal nerve ligation model of Kim and Chung 17 ; i.p. intraperitoneal dosing; i.t. intrathecal dosing (onto the surface of the lumbar spinal cord); heat heat-hyperalgesia; spon spontaneous pain behaviors; M-allo mechano-allodynia. the absence of opiate treatment. Conversely, opiate tolerance appears to engage intracellular events similar to those engaged by painevoked NMDA-receptor activation. Thus, the opiate-tolerant patient has a central sensitization like hyperalgesia. Conclusion The resistance of certain kinds of pain to opiate analgesia, or tolerance, was generally thought to involve simple receptor downregulation. We now know that the mechanisms of tolerance interact directly with pain sensitivity. Understanding these mechanisms, which include glutamate-mediated activation of NMDA receptors, points to the possibility of improving opiate analgesic therapy with the co-administration of an NMDA-receptor antagonist. References 1. Bennett GJ. Neuropathic pain. In: Wall PD, Melzack R, eds. Textbook of pain, 3rd ed. Edinburgh, London: Churchill Livingstone, 1994: Meyer RA, Campbell JN, Raja SN. Peripheral neural mechanisms of nociception. In: Wall PD, Melzack R, eds. Textbook of pain, 3rd ed. Edinburgh, London: Churchill Livingstone, 1994: Sato J, Suzuki S, Iseki T, et al. Adrenergic excitation of cutaneous nociceptors in chronically inflamed rats. Neurosci Lett 1993;164: Kajander KC, Bennett GJ. The onset of a painful peripheral neuropathy in rat: a partial and differential deafferentation and spontaneous discharge in A-beta and A-delta primary afferent neurons. J Neurophysiol 1992;68: Devor M. The pathophysiology of damaged peripheral nerves. In: Wall PD, Melzack R, eds. Textbook of pain, 3rd ed. Edinburgh, London: Churchill Livingstone, 1994: Perl ER. A reevaluation of mechanisms leading to sympathetically related pain. In: Fields HL, et al., eds. Pharmacological approaches to the treatment of chronic pain: new concepts and critical issues. Seattle, WA: IASP Press, 1994: Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation: implications for the treatment of post-injury pain hypersensitivity states. Pain 1991;44: Gracely RH, Lynch S, Bennett GJ. Painful neuropathy: altered central processing, maintained dynamically by peripheral input. Pain 1992;51: LaMotte RH, Shain CN, Simone DA, et al. Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms. J Neurophysiol 1991;66: Sang CN, Gracely RH, Max, MB, et al. Capsaicinevoked mechanical allodynia and hyperalgesia cross nerve territories: evidence for a central mechanism. Anesthesiol 1996;85: Liu M, Max MB, Robinovitz E, et al. The human capsaicin model of allodynia and hyperalgesia: sources of variability and methods for reduction. J Pain Symptom Manage 1998;16: Sethna N, Liu M, Gracely R, et al. Analgesic and
5 S6 Bennett Vol. 19 No. 1(Suppl.) January 2000 cognitive effects of intravenous ketamine-alfentanil combinations vs. either drug alone after intradermal capsaicin in normal subjects. Anesth Analg 1998;86: Bennett GJ, Xie Y-K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33: Davar G, Hama A, Deykin A., Vos B, Maciewicz R. MK-801 blocks the development of thermal hyperalgesia in a rat model of experimental painful neuropathy. Brain Res 1991;553: Yamamoto T, Yaksh TL. Spinal pharmacology of thermal hyperesthesia induced by constriction injury of sciatic nerve: excitatory amino acid antagonists. Pain 1992;49: Mao J, Price DD, Mayer DJ, Lu J, Hayes RL. Intrathecal MK 801 and local nerve anesthesia synergistically reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy. Brain Res 1992;576: Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992;50: Chaplan SR, Malmberg AB, Yaksh, TL. Efficacy of spinal NMDA-receptor antagonism in formalin hyperalgesia and nerve injury evoked allodynia in the rat. Pharmacol Exp Therap 1997;280: Tal M, Bennett GJ. Neuropathic pain sensations are differentially sensitive to dextrorphan. NeuroReport 1994;5: Mao J, Price DD, Hayes RL, Lu J, Mayer DJ, Frenk H. Intrathecal treatment with dextrorphan or ketamine potently reduces pain-related behaviours in a rat model of peripheral mononeuropathy. Brain Res 1993;605: Eisenberg E, LaCross S, Strassman AM. The clinically tested N-methyl-D-aspartate receptor antagonist memantine blocks and reverses thermal hyperalgesia in a rat model of painful mononeuropathy. Neurosci Lett 1995;187: Xiao W-H, Bennett GJ. Magnesium suppresses abnormal pain responses via a spinal site of action in rats with an experimental peripheral neuropathy. Brain Res 1994;666: Eide PK, Jorum E, Stubhaug A, et al. Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. Pain 1994;58: Max MB, Byas-Smith MG, Gracely RH, et al. Intravenous infusion of the NMDA antagonists, ketamine, in chronic post-traumatic pain and allodynia: a double-blind comparison with alfentanil and placebo. Clin Neuropharmacol 1995;18: Persson J, Axelsson G, Hallin RG, et al. Beneficial effects of ketamine in a chronic pain state with allodynia, possibly due to central sensitization. Pain 1995;60: Nelson KA, Park KM, Robinovitz E, et al. Highdose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurol 1997;48: Eisenberg E, Pud D. Can patients with chronic neuropathic pain be cured by acute administration of the NMDA-receptor antagonist amantadine? Pain 1994;74:37 39.
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