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5b - The physiology of neuropathic pain

from Section 2 - Cancer Symptom Mechanisms and Models: Clinical and Basic Science

Published online by Cambridge University Press:  05 August 2011

By
Haijun Zhang  and
Patrick M. Dougherty
Edited by
Charles S. Cleeland ,
Michael J. Fisch  and
Adrian J. Dunn
Haijun Zhang
Affiliation:
The University of Texas M. D. Anderson Cancer Center
Patrick M. Dougherty
Affiliation:
The University of Texas M. D. Anderson Cancer Center
Charles S. Cleeland
Affiliation:
University of Texas, M. D. Anderson Cancer Center
Michael J. Fisch
Affiliation:
University of Texas, M. D. Anderson Cancer Center
Adrian J. Dunn
Affiliation:
University of Hawaii, Manoa
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Summary

The International Association for the Study of Pain (IASP) defines pain as “an unpleasant, sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” The pain that is commonly experienced by people with cancer may be caused by the disease itself or by cancer treatment. The three most common causes for cancer pain are: (1) tumors metastasizing to the bone; (2) tumors infiltrating the nerve and hollow viscus; and (3) cancer treatments such as chemotherapy, radiation, and surgery. Cancer pain thus involves multiple mechanisms, including inflammation and primary and secondary hyperalgesia after tissue or nerve injury.

In this chapter, we will describe the basic physiology of pain signal processing, including peripheral nociceptors that sense stimuli in multiple energy forms (eg, heat, mechanical, chemical) and central stations involved in coding pain sensibility. We will describe the mechanisms of primary and secondary hyperalgesia wherein normally innocuous stimuli become painful. Finally, we will discuss some of the alterations in the functions of neurons and nonneuronal cells when the nervous system itself is damaged.

Peripheral and central mechanisms of nociception

Peripheral nociceptors

Nociception – the ability to feel pain – is caused by activation of peripheral receptors known as nociceptors. Nociceptors respond selectively to a variety of noxious stimuli, such as heat, pinch, and chemicals, and provide information about the location and intensity of such stimuli. Nociceptors can be categorized into three classes according to their structural and functional properties.

Type
Chapter
Information
Cancer Symptom Science
Measurement, Mechanisms, and Management
 , pp. 41 - 50
Publisher: Cambridge University Press
Print publication year: 2010

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References

Merskey, H, Bogduk, N. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, 2nd ed. Seattle: IASP Press, 1994.Google Scholar
Campbell, JN, LaMotte, RH. Latency to detection of first pain. Brain Res 266(2):203–208, 1983.CrossRefGoogle ScholarPubMed
Meyer, RA, Campbell, JN. Peripheral neural coding of pain sensation. J H A P L Tech Digest 2:164–171, 1981.Google Scholar
Torebjörk, HE, LaMotte, RH, Robinson, CJ. Peripheral neural correlates of magnitude of cutaneous pain and hyperalgesia: simultaneous recordings in humans of sensory judgments of pain and evoked responses in nociceptors with C-fibers. J Neurophysiol 51(2):325–339, 1984.CrossRefGoogle ScholarPubMed
Willis, WD. The Pain System: the Neural Basis of Nociceptive Transmission in the Mammalian Nervous System. Basel: Karger, 1985. Pain and Headache; vol. 8.Google ScholarPubMed
Willis, WD, Coggeshall, RE. Sensory Mechanisms of the Spinal Cord, 2nd ed. New York: Plenum Press, 1991.CrossRefGoogle Scholar
Cata, JP, Weng, HR, Dougherty, PM. Basic neurobiology of cancer pain. In: Fisch, MJ, Burton, AW, eds. Cancer Pain Management. New York: McGraw-Hill, Medical Pub. Division, 2007:57–74.Google Scholar
Rexed, B. The cytoarchitectonic organization of the spinal cord in the cat. J Comp Neurol 96(3):414–495, 1952.CrossRefGoogle ScholarPubMed
Dougherty, PM, Palecek, J, Palecková, V, Sorkin, LS, Willis, WD. The role of NMDA and non-NMDA excitatory amino acid receptors in the excitation of primate spinothalamic tract neurons by mechanical, thermal, chemical, and electrical stimuli. J Neurosci 12:3025–3041, 1992.CrossRefGoogle ScholarPubMed
Dougherty, PM, Willis, WD. Enhanced responses of spinothalamic tract neurons to excitatory amino acids accompany capsaicin-induced sensitization in the monkey. J Neurosci 12(3):883–894, 1992.CrossRefGoogle ScholarPubMed
Craig, AD, Hunsley, SJ. Morphine enhances the activity of thermoreceptive cold-specific lamina I spinothalamic neurons in the cat. Brain Res 558(1):93–97, 1991.CrossRefGoogle ScholarPubMed
Handwerker, HO, Kobal, G. Psychophysiology of experimentally induced pain. Physiol Rev 73(3):639–671, 1993.CrossRefGoogle ScholarPubMed
Al-Chaer, ED, Feng, Y, Willis, WD. A role for the dorsal column in nociceptive visceral input into the thalamus of primates. J Neurophysiol 79(6):3143–3150, 1998.CrossRefGoogle ScholarPubMed
Woolf, CJ, Salter, MW. Neuronal plasticity: increasing the gain in pain. Science 288(5472):1765–1769, 2000.CrossRefGoogle ScholarPubMed
Lewis, T. Pain. New York: The Macmillan Company, 1942.Google Scholar
LaMotte, RH, Thalhammer, JG, Torebjörk, HE, Robinson, CJ. Peripheral neural mechanisms of cutaneous hyperalgesia following mild injury by heat. J Neurosci 2(6):765–781, 1982.CrossRefGoogle ScholarPubMed
Meyer, RA, Campbell, JN. Myelinated nociceptive afferents account for the hyperalgesia that follows a burn to the hand. Science 213(4515):1527–1529, 1981.CrossRefGoogle Scholar
LaMotte, RH, Thalhammer, JG, Robinson, CJ. Peripheral neural correlates of magnitude of cutaneous pain and hyperalgesia: a comparison of neural events in monkey with sensory judgments in human. J Neurophysiol 50(1):1–26, 1983.CrossRefGoogle ScholarPubMed
Grigg, P, Schaible, HG, Schmidt, RF. Mechanical sensitivity of group III and IV afferents from posterior articular nerve in normal and inflamed cat knee. J Neurophysiol 55(4):635–643, 1986.CrossRefGoogle ScholarPubMed
Davis, KD, Meyer, RA, Campbell, JN. Chemosensitivity and sensitization of nociceptive afferents that innervate the hairy skin of monkey. J Neurophysiol 69(4):1071–1081, 1993.CrossRefGoogle ScholarPubMed
Schmelz, M, Schmidt, R, Ringkamp, M, Handwerker, HO, Torebjörk, HE. Sensitization of insensitive branches of C nociceptors in human skin. J Physiol 480(Pt 2):389–394, 1994.CrossRefGoogle ScholarPubMed
Simone, DA, Sorkin, LS, Oh, U, et al. Neurogenic hyperalgesia: central neural correlates in responses of spinothalamic tract neurons. J Neurophysiol 66(1):228–246, 1991.CrossRefGoogle ScholarPubMed
Woolf, CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature 306(5944):686–688, 1983.CrossRefGoogle ScholarPubMed
Dougherty, PM, Willis, WD, Lenz, FA. Transient inhibition of responses to thermal stimuli of spinal sensory tract neurons in monkeys during sensitization by intradermal capsaicin. Pain 77(2):129–136, 1998.CrossRefGoogle ScholarPubMed
Meyer, RA, Raja, SN, Campbell, JN. Neural mechanisms of primary hyperalgesia. In: Belmonte, C, Cervero, F, eds. Neurobiology of Nociceptors. Oxford: Oxford University Press, 1996:370–389.Google Scholar
Kress, M, Reeh, RW. Chemical excitation and sensitization in nociceptors. In: Belmonte, C, Cervero, F, eds. Neurobiology of Nociceptors. Oxford: Oxford University Press, 1996:258–297.Google Scholar
Roberts, WJ, Elardo, SM. Sympathetic activation of unmyelinated mechanoreceptors in cat skin. Brain Res 339(1):123–125, 1985.CrossRefGoogle ScholarPubMed
Campbell, JN, Khan, AA, Meyer, RA, Raja, SN. Responses to heat of C-fiber nociceptors in monkey are altered by injury in the receptive field but not by adjacent injury. Pain 32(3):327–332, 1988.CrossRefGoogle Scholar
Campbell, JN, Raja, SN, Meyer, RA, Mackinnon, SE. Myelinated afferents signal the hyperalgesia associated with nerve injury. Pain 32(1):89–94, 1988.CrossRefGoogle ScholarPubMed
Laird, JM, Bennett, GJ. An electrophysiological study of dorsal horn neurons in the spinal cord of rats with an experimental peripheral neuropathy. J Neurophysiol 69(6):2072–2085, 1993.CrossRefGoogle ScholarPubMed
Palecek, J, Dougherty, PM, Kim, SH, et al. Responses of spinothalamic tract neurons to mechanical and thermal stimuli in an experimental model of peripheral neuropathy in primates. J Neurophysiol 68(6):1951–1966, 1992.CrossRefGoogle Scholar
Albe-Fessard, DA, Rampin, O. Neurophysiological studies in rats deafferented by dorsal root section. In: Nashold, BS, Ovelmen-Levitt, J, eds. Deafferentation Pain Syndromes: Pathophysiology and Treatment. New York: Raven Press, 1991:125–139. Advances in Pain Research and Therapy; vol. 19.Google Scholar
Lenz, FA, Gracely, RH, Baker, FH, Richardson, RT, Dougherty, PM. Reorganization of sensory modalities evoked by microstimulation in region of the thalamic principal sensory nucleus in patients with pain due to nervous system injury. J Comp Neurol 399(1):125–138, 1998.3.0.CO;2-G>CrossRefGoogle ScholarPubMed
Kaas, JH, Merzenich, MM, Killackey, HP. The reorganization of somatosensory cortex following peripheral nerve damage in adult and developing mammals. Annu Rev Neurosci 6:325–356, 1983.CrossRefGoogle ScholarPubMed
Pons, TP, Garraghty, PE, Ommaya, AK, Kaas, JH, Taub, E, Mishkin, M. Massive cortical reorganization after sensory deafferentation in adult macaques. Science 252(5014):1857–1860, 1991.CrossRefGoogle ScholarPubMed
Wall, JT, Cusick, CG. Cutaneous responsiveness in primary somatosensory (S-I) hindpaw cortex before and after partial hindpaw deafferentation in adult rats. J Neurosci 4(6):1499–1515, 1984.CrossRefGoogle ScholarPubMed
Melzack, R, Wall, PD. Pain mechanisms: a new theory. Science 150(699):971–979, 1965.CrossRefGoogle ScholarPubMed
Bennett, GJ, Kajander, KC, Sahara, Y, Iadarola, MJ, Sugimoto, T. Neurochemical and anatomical changes in the dorsal horn of rats with an experimental painful peripheral neuropathy. In: Cervero, F, Bennett, GJ, Headley, PM, eds. Processing of Sensory Information in the Superficial Dorsal Horn of the Spinal Cord. New York: Plenum Press, 1989:1–23. NATO ASI Series: Series A, Life Sciences; vol. 176.Google Scholar
Ralston, DD, Dougherty, PM, Lenz, FA, Weng, HR, Vierck, CJ, Ralston, HJ. Plasticity of the inhibitory circuits of the primate ventrobasal thalamus following lesions of the somatosensory pathways. In: Devor, M, Rowbotham, MC, Wiesenfeld-Hallin, Z, eds. Proceedings of the 9th World Congress on Pain. Seattle: IASP Press, 2000:427–434. Progress in Pain Research and Management; vol. 16.Google Scholar
Watkins, LR, Maier, SF. Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2(12):973–985, 2003.CrossRefGoogle ScholarPubMed
Zhuang, ZY, Gerner, P, Woolf, CJ, Ji, RR. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 114(1–2):149–159, 2005.CrossRefGoogle ScholarPubMed
Meller, ST, Dykstra, C, Grzybycki, D, Murphy, S, Gebhart, GF. The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat. Neuropharmacology 33(11):1471–1478, 1994.CrossRefGoogle ScholarPubMed
Watkins, LR, Martin, D, Ulrich, P, Tracey, KJ, Maier, SF. Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain 71(3):225–235, 1997.CrossRefGoogle ScholarPubMed
Inoue, K, Tsuda, M, Koizumi, S. ATP receptors in pain sensation: involvement of spinal microglia and P2X(4) receptors. Purinergic Signal 1(2):95–100, 2005.CrossRefGoogle ScholarPubMed
Zhuang, ZY, Kawasaki, Y, Tan, PH, Wen, YR, Huang, J, Ji, RR. Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain Behav Immun 21(5):642–651, 2007.CrossRefGoogle ScholarPubMed
Jin, SX, Zhuang, ZY, Woolf, CJ, Ji, RR. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci 23(10):4017–4022, 2003.CrossRefGoogle ScholarPubMed
Tsuda, M, Mizokoshi, A, Shigemoto-Mogami, Y, Koizumi, S, Inoue, K. Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia 45(1):89–95, 2004.CrossRefGoogle ScholarPubMed
Sweitzer, S, Martin, D, DeLeo, JA. Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain. Neuroscience 103(2):529–539, 2001.CrossRefGoogle Scholar
Watkins, LR, Hutchinson, MR, Johnston, IN, Maier, SF. Glia: novel counter-regulators of opioid analgesia. Trends Neurosci 28(12):661–669, 2005.CrossRefGoogle ScholarPubMed
Milligan, ED, Twining, C, Chacur, M, et al. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci 23(3):1026–1040, 2003.CrossRefGoogle ScholarPubMed
Milligan, ED, Watkins, LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10(1):23–36, 2009.CrossRefGoogle ScholarPubMed
Zhuang, ZY, Wen, YR, Zhang, DR, et al. A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 26(13):3551–3560, 2006.CrossRefGoogle ScholarPubMed
Conti, G, Pol, A, Scarpini, E, et al. Interleukin-1 beta and interferon-gamma induce proliferation and apoptosis in cultured Schwann cells. J Neuroimmunol 124(1–2):29–35, 2002.CrossRefGoogle ScholarPubMed
Shubayev, VI, Myers, RR. Endoneurial remodeling by TNFalph- and TNFalpha-releasing proteases: A spatial and temporal co-localization study in painful neuropathy. J Peripher Nerv Syst 7(1):28–36, 2002.CrossRefGoogle ScholarPubMed

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