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Mechanisms of Central Sensitization of Nociceptive Dorsal Horn Neurons

  • William D. WillisJr.

Abstract

An important theme in contemporary research on the nervous system is plasticity. The activity of the nervous system is in part dependent on its past activity, which implies that neural responses can be modified by prior events. The mechanisms that are thought to underlie many forms of learning and memory, such as long-term potentiation (LTP) and long-term depression (LTD), typify this type of plasticity (Riedel, et al., 1996; Thompson, et al., 1997; Daniel, et al., 1998; however, cf. Hölscher, 1997). Plasticity occurs not only in the brain, but also in the spinal cord (Windhorst, 1996; Willis, 1997), as is emphasized in this symposium volume. For example, electrophysiological response changes similar to LTP and LTD have been described in the spinal cord, both in vivo and in vitro (Randic, et al., 1993; Svendsen, et al., 1997; Liu and Sandkuhler, 1997; Sandkuhler and Liu, 1998), and rewiring of the afferent connections to the dorsal horn has been demonstrated following peripheral nerve injury (Woolf, et al., 1992). Many workers in the field of pain research refer to the form of spinal cord plasticity that will be discussed in this chapter as central sensitization and suggest that this process underlies such abnormal pain states as secondary hyperalgesia and allodynia (Woolf, 1992; Willis, 1993; cf., Kenshalo, et al., 1982; Woolf, 1983; Yaksh, 1989; Dubner and Ruda, 1992).

Keywords

Central Sensitization Intradermal Injection Spinothalamic Tract Inhibitory Amino Acid Secondary Hyperalgesia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Ali, Z., Meyer, R.A. and Campbell, J.N. Secondary hyperalgesia to mechanical but not heat stimuli following a capsaicin injection in hairy skin. Pain, 1996; 68:401–411.PubMedCrossRefGoogle Scholar
  2. Andrews, K., Baranowski, A., and Kinnman, E. Sensory threshold changes without initial pain or alterations in cutaneous blood flow, in the area of secondary hyperalgesia caused by topical application of capsaicin in humans. Neuroscience Letters 266:45–48, 1999.PubMedCrossRefGoogle Scholar
  3. Baumann, T.K., Simone, D.A., Shain, C.N. and LaMotte, R.H. Neurogenic hyperalgesia: The search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia. Journal of Neurophysiology, 1991; 66:212–227.PubMedGoogle Scholar
  4. Blair, R.W., Weber, R.N. and Foreman, R.D. Characteristics of primate spinothalamic tract neurons receiving viscerosomatic convergent input in T3-T5 segments. Journal of Neurophysiology, 1981;46:797–811.PubMedGoogle Scholar
  5. Bredt, D.S. and Snyder, S.H. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proceedings of The National Academy of Sciences of the United States of America, 1989; 86:9030–9033.PubMedCrossRefGoogle Scholar
  6. Carpenter, S.E. and Lynn, B. Vascular and sensory responses of human skin to mild injury after topical treatment with capsaicin. British Journal of Pharmacology, 1981; 73:755–758.PubMedCrossRefGoogle Scholar
  7. Cervero, F., Meyer, R.A. and Campbell, J.N. A psychophysical study of secondary hyperalgesia: evidence for increased pain to input from nociceptors. Pain, 1994; 58:21–28.PubMedCrossRefGoogle Scholar
  8. Chen, L. and Huang, L.Y.M. Sustained potentiation of NMDA receptor-mediated glutamate responses through activation of protein kinase C by a u opioid. Neuron, 1991; 7:319–326.PubMedCrossRefGoogle Scholar
  9. Chen, L. and Huang, L.Y.M. Protein kinase C reduced Mg++ block of NMDA-receptor channels as a mechanism of modulation. Nature, 1992; 356:521–523.PubMedCrossRefGoogle Scholar
  10. Chung, J.M., Kenshalo, D.R., Gerhart, K.D. and Willis, W.D. Excitation of primate spinothalamic neurons by cutaneous C-fiber volleys. Journal of Neurophysiology, 1979; 42:1354–1369.PubMedGoogle Scholar
  11. Chung, J.M., Surmeier, D.J., Lee, K.H., Sorkin, L.S., Honda, C.N., Tsong, Y. and Willis, W.D. Classification of primate spinothalamic and somatosensory thalamic neurons based on cluster analysis. Journal of Neurophysiology, 1986; 56:308–327.PubMedGoogle Scholar
  12. Coderre, T.J. Contribution of protein kinase C to central sensitization and persistent pain following tissue injury. Neuroscience Letters, 1992; 140:181–184.PubMedCrossRefGoogle Scholar
  13. Conn, P.J., Boss, V. and Chung, D.S. (1994). Second-messenger systems coupled to metabotropic glutamate receptors. In: P.J. Conn and J. Patel (Eds.), The Metabotropic Glutamate Receptors (pp. 59–98). Totowa, N.J.: Human Press Inc.Google Scholar
  14. Cui, M., Feng, Y., McAdoo, D.J. and Willis, W.D. Periaqueductal gray stimulation-induced inhibition of nociceptive dorsal horn neurons in rats is associated with the release of norepinephrine, serotonin, and amino acids. Journal of Pharmacology and Experimental Therapeutics, 1999; 289:868–876.PubMedGoogle Scholar
  15. Daniel, H., Levenes, C. and Crepel, F. Cellular mechanisms of cerebellar LTD. Trends in Neuroscience, 1998;21:401–407.CrossRefGoogle Scholar
  16. Davies, S.N. and Lodge, D. Evidence for involvement of N-methylaspartate receptors in ‘wind-up’ of class 2 neurones in the dorsal horn of the rat. Brain Research, 1987; 424:402–406.PubMedCrossRefGoogle Scholar
  17. De Biasi, S. and Rustioni, A. Glutamate and substance P coexist in primary afferent terminals in the superficial laminae of spinal cord. Proceedings of The National Academy of Sciences of the United States of America, 1988; 85:7820–7824.PubMedCrossRefGoogle Scholar
  18. Dickenson, A.H. and Sullivan, A.F. Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacology, 1987; 26:1235–1238.PubMedCrossRefGoogle Scholar
  19. Dingledine, R., Borges, K., Bowie, D. and Traynelis, S.F. The glutamate receptor ion channels. Pharmacology Review 51:7–61, 1999.Google Scholar
  20. Dougherty, P.M. and Willis, W.D. Enhancement of spinothalamic neuron responses to chemical and mechanical stimuli following combined micro-iontophoretic application of N-methyl-D-aspartic acid and substance P. Pain, 1991; 47:85–93.PubMedCrossRefGoogle Scholar
  21. Dougherty P.M. and Willis, W.D. Enhanced responses of spinothalamic tract neurons to excitatory amino acids accompany capsaicin-induced sensitization in the monkey. Journal of Neuroscience, 1992; 12:883–894.PubMedGoogle Scholar
  22. Dougherty, P.M., Palecek, J., Paleckova, V., Sorkin, L.S. and Willis, W.D. The role of NMDA and non-NMDA excitatory amino acid receptors in the excitation of primate spinothalamic tract neurons by mechanical, chemical, thermal, and electrical stimuli. Journal of Neuroscience, 1992; 12:3025–3041.PubMedGoogle Scholar
  23. Dougherty, P.M., Palecek, J., Paleckova, V. and Willis, W.D. Neurokinin 1 and 2 antagonists attenuate the responses and NK1 antagonists prevent the sensitization of primate spinothalamic tract neurons after intradermal capsaicin. Journal of Neurophysiology, 1994; 72:1464–1475.PubMedGoogle Scholar
  24. Dougherty, P.M., Palecek, J., Zorn, S. and Willis, W.D. Combined application of excitatory amino acids and substance P produces long-lasting changes in responses of primate spinothalamic tract neurons. Brain Research Review, 1993; 18:227–246.CrossRefGoogle Scholar
  25. Dubner R. and Ruda, M.A. Activity-dependent neuronal plasticity following tissue injury and inflammation. Trends in Neuroscience, 1992; 15:96–103.CrossRefGoogle Scholar
  26. Gamse, R., Molnar, A. and Lembeck, F. Substance P release from spinal cord slices by capsaicin. Life Sciences, 1979; 25:629–636.PubMedCrossRefGoogle Scholar
  27. Glaum, S.R. and Miller, R.J. Activation of metabotropic glutamate receptors produces reciprocal regulation of ionotropic glutamate and GABA responses in the nucleus of the tractus-solitarius of the rat. Journal of Neuroscience, 1993; 13:1636–1641.PubMedGoogle Scholar
  28. Hardy, J.D., Wolff, H.G. and Goodell, H. Pain sensations and reactions. The Williams & Wilkins Co., N.Y., 1952; reprinted by Hafner Publishing Company, Inc., New York, 1967.Google Scholar
  29. Herdegen, T. and Leah, J.D. Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins. Brain Research Review, 1998; 28:370–490.CrossRefGoogle Scholar
  30. Herz, A., Zieglgänsberger, W. and Färber, G. Microelectrophoretic studies concerning the spread of glutamic acid and GABA in brain tissue. Experimental Brain Research, 1969; 9:221–235.CrossRefGoogle Scholar
  31. Hölscher, C. Long-term potentiation: a good model for learning and memory? Progress In Neuro-Psychopharmacology and Biological Psychiatry, 1997; 21:47–68.CrossRefGoogle Scholar
  32. Jeftinija, S. and Urban, L. Repetitive stimulation induced potentiation of excitatory transmission in the rat dorsal horn: an in vitro study. Journal of Neurophysiology, 1994; 71:216–228.PubMedGoogle Scholar
  33. Ji, R.R. and Rupp, F. Phosphorylation of transcription factor CREB in rat spinal cord after formalin-induced hyperalgesia: relationship to c-fos induction. Journal of Neuroscience, 1997; 17:1776–1785.PubMedGoogle Scholar
  34. Kenshalo, D.R., Leonard, R.B., Chung, J.M. and Willis, W.D. Facilitation of the responses of primate spinothalamic cells to cold and to tactile stimuli by noxious heating of the skin. Pain, 1982; 12:141–152.PubMedCrossRefGoogle Scholar
  35. Kitto, K.F., Haley, J.E. and Wilcox, G.L. Involvement of nitric oxide in spinally mediated hyperalgesia in the mouse. Neuroscience Letters, 1992; 148:1–5.PubMedCrossRefGoogle Scholar
  36. Koltzenburg, M., Lundberg, L.E.R. and Torebjörk, H.E. Dynamic and static components of mechanical hyperalgesia in human hairy skin. Pain, 1992; 51:207–219.PubMedCrossRefGoogle Scholar
  37. Krause, J.E., Sachais, B.S. and Blount, P. Tachykinin. (1994). Receptors. In Peroutka, S.J (Ed.), Handbook of Receptors and Channels; G Protein Coupled Receptors. Boca Raton: CRC Press.Google Scholar
  38. LaMotte, R.H., Lundberg, L.E.R. and Torebjörk, H.E. Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin. Journal of Physiology, 1992; 448:749–764.PubMedGoogle Scholar
  39. LaMotte, R.H., Shain, C.H., Simone, D.A. and Tsai, E.F.P. Neurogenic hyperalgesia: Psychophysical studies of underlying mechanisms. Journal of Neurophysiology, 1991; 66:190–211.PubMedGoogle Scholar
  40. Leidenheimer, N.J., McQuilkin, S.J., Hahner, L.D., Whiting, P. and Harris, R.A. Activation of protein-kinase-C selectively inhibits the gamma-aminobutyric acidA receptor: role of desensitization. Molecular Pharmacology, 1992; 41:1116–1123.PubMedGoogle Scholar
  41. Lewis, T. The blood vessels of the human skin and their responses. Shaw & Sons Ltd., London, 1927.Google Scholar
  42. Lewis, T. Pain. The Macmillan Press Ltd, London, 1942.Google Scholar
  43. Lin, Q., Palecek, J., Paleckova, V., Peng, Y.B., Wu, J., Cui, M. and Willis, W.D. Nitric oxide mediates the central sensitization of primate spinothalamic tract neurons. Journal of Neurophysiology, 1999;81:1075–1085.PubMedGoogle Scholar
  44. Lin, Q., Peng, Y.B. and Willis, W.D. Inhibition of primate spinothalamic tract neurons by spinal glycine and GABA is reduced during central sensitization. Journal of Neurophysiology, 1996a; 76:1005–1014.Google Scholar
  45. Lin, Q., Peng, Y.B. and Willis, W.D. Antinociception and inhibition from the periaqueductal gray are mediated in part by spinal 5-hydroxytryptamineiA receptors. Journal of Pharmacology and Experimental Therapeutics, 1996b; 276:958–967.Google Scholar
  46. Lin, Q., Peng, Y.B. and Willis, W.D. Possible role of protein kinase C in the sensitiization of primate spinothalamic tract neurons. Journal of Neuroscience, 1996c; 16:3026–3034.Google Scholar
  47. Lin, Q., Peng, Y.B., Wu, J. and Willis, W.D. Involvement of cGMP in nociceptive processing by and sensitization of spinothalamic neurons in primates. Journal of Neuroscience, 1997; 17:3293–3302.PubMedGoogle Scholar
  48. Lin, Q., Wu, J., Cui, M. and Willis, W.D. Protein kinase A sensitizes primate spinothalamic tract neurons by influencing spinal excitatory and inhibitory amino acid receptors. Neuroscience Abstracts, 1998; 24:637.Google Scholar
  49. Lin, Q., Wu, J., Peng, Y.B., Cui, M. and Willis, W.D. Nitric oxide-mediated spinal disinhibition contributes to the sensitization of primate spinothalamic tract neurons. Journal of Neurophysiology, 1999a; 81:1086–1094.Google Scholar
  50. Lin, Q., Wu, J., Peng, Y.B., Cui, M. and Willis, W.D. Inhibition of primate spinothalamic tract neurons by spinal glycine and GABA is modulated by guanosine 3′, 5′-cyclic monophosphate. Journal of Neurophysiology, 1999b; 81:1095–1103.Google Scholar
  51. Lin, Q., Wu, J. and Willis, W.D. The effect of protein kinase A activation on the responses of primate spinothalamic neurons to mechanical and thermal stimuli. Neuroscience Abstracts, 1997; 23:2357.Google Scholar
  52. Lincoln, T.M., Komalavilas, P. and Cornwell, T.L. Pleiotropic regulation of vascular smooth muscle tone by cyclic GMP-dependent protein kinase. Hypertension, 1994; 23:1141–1147.PubMedCrossRefGoogle Scholar
  53. Linden, D.R. and Seybold, V.S. Spinal neurokinin receptors mediate thermal but not mechanical hyperalgesia via nitric oxide. Pain, 1999; 80:309–317.PubMedCrossRefGoogle Scholar
  54. Liu, X. and Sandkuhler, J. Characterization of long-term potentiation of C-fiber-evoked potentials in spinal cord dorsal horn of adult rat: essential role of NK1 and NK2 receptors. Journal of Neurophysiology, 1997; 78:1973–1982.PubMedGoogle Scholar
  55. Malmberg, A.B., Brandon, E.P., Idzerda, R.L., Liu, H., McKnight, G.S. and Basbaum, A.I. Diminished inflammation and nociceptive pain with preservation of neuropathic pain in mice with a targeted mutation of the type I regulatory subunit of cAMP-dependent protein kinase. Journal of Neuroscience, 1997; 17:7462–7470.PubMedGoogle Scholar
  56. Malmberg, A.B., Chen, C., Tonegawa, S. and Basbaum, A.I. Preserved acute pain and reduced neuropathic pain in mice lacking PKCgamma. Science, 1997; 278:279–283.PubMedCrossRefGoogle Scholar
  57. Mao, J., Mayer, D.J., Hayes, R.L. and Price, D.D. Spatial patterns of increased spinal cord membrane-bound protein kinase C and their relation to increases in 14C-2-deoxyglucose metabolic activity in rats with painful peripheral mononeuropathy. Journal of Neurophysiology, 1993; 70:470–481.PubMedGoogle Scholar
  58. McEachern, J.C. and Shaw, C.A. An alternative to the LTP orthodoxy: a plasticity-pathology continuum model. Brain Research Review, 1996; 22:51–92.CrossRefGoogle Scholar
  59. Melier, S.T. and Gebhart, G.F. Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain, 1993;52:127–136.CrossRefGoogle Scholar
  60. Meiler, S.T., Cummings, C.P., Traub, R.J. and Gebhart, G.F. The role of nitric oxide in the development and maintenance of the hyperalgesia produced by intraplantar injection of carrageenan in the rat. Neuroscience, 1994; 60:367–374.CrossRefGoogle Scholar
  61. Meiler, S.T., Pechman, P.S., Gebhart, G.F. and Maves, T.J. Nitric oxide mediates the thermal hyperalgesia produced in a model of neuropathic pain in the rat. Neuroscience, 1992; 50:7–10.CrossRefGoogle Scholar
  62. Mendell, L.M. Physiological properties of unmyelinated fiber projection to the spinal cord. Experimental Neurology, 1966; 16:316–332.PubMedCrossRefGoogle Scholar
  63. Merskey, H. and Bogduk, N. (Eds.) Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. 2nd ed. IASP Press, Seattle, 1994.Google Scholar
  64. Meyer, R.A. and Campbell, J.N. Myelinated nociceptive afferents account for the hyperalgesia that follows a burn to the hand. Science, 1981; 213:1527–1529.PubMedCrossRefGoogle Scholar
  65. Moore, P.K., Babbedge, R.C., Wallace, P., Gaffen, Z.A. and Hart, S.L. 7-nitro indazole, an inhibitor of nitric oxide synthase, inhibits anti-nociceptive activity in the mouse without increasing blood pressure. British Journal of Pharmacology, 1993; 108:296–297.PubMedCrossRefGoogle Scholar
  66. Nagy, I., Maggi, C.A., Dray, A., Woolf, C.J. and Urban, L. The role of neurokinin and N-methyl-D-aspartate receptors in synaptic transmission from capsaicin sensitive primary afférents in the rat spinal cord in vitro. Neuroscience, 1993; 52:1029–1037.PubMedCrossRefGoogle Scholar
  67. Nagy, I., Miller, B.A. and Woolf, C.J. NKi and NK2 receptors contribute to C-fibre evoked slow potentials in the rat spinal cord. Neuroreport, 1994; 5:2105–2108.PubMedCrossRefGoogle Scholar
  68. Nakanishi, S. Mammalian tachykinin receptors. Annual Review of Neuroscience, 1991; 14:123–136.PubMedCrossRefGoogle Scholar
  69. Neugebauer, V., Chen, P.S. and Willis, W.D. Role of metabotropic glutamate receptor subtype mGluRl in brief nociception and central sensitization of primate STT cells. Journal of Neurophysiology, 1999; 82: 272–282.PubMedGoogle Scholar
  70. Palecek, J., Paleckova, V., Dougherty, P.M. and Willis, W.D. The effect of phorbol esters on the responses of primate spinothalamic neurons to mechanical and thermal stimuli. Journal of Neurophysiology, 1994; 71:529–537.PubMedGoogle Scholar
  71. Palecek, J., Paleckova, V. and Willis, W.D. The effect of phorbol esters on spinal cord amino acid concentrations and responsiveness of rats to mechanical and thermal stimuli. Pain, 1999; 80:597–605.PubMedCrossRefGoogle Scholar
  72. Peng, Y.B., Lin, Q. and Willis, W.D. The role of 5-HT3 receptors in periaqueductal gray-induced inhibition of nociceptive dorsal horn neurons in rats. Journal of Pharmacology and Experimental Therapeutics, 1996a; 276:116–124.Google Scholar
  73. Peng, Y.B., Lin, Q. and Willis, W.D. Involvement of alpha-2 adrenoreceptors in the periaqueductal gray-induced inhibition of dorsal horn cell activity in rats. Journal of Pharmacology and Experimental Therapeutics, 1996b; 278:125–135.Google Scholar
  74. Peng, Y.B., Lin, Q. and Willis, W.D. Effects of GABA and glycine receptor antagonists on the activity and PAG-induced inhibition of rat dorsal horn neurons. Brain Research, 1996c; 736:189–201.CrossRefGoogle Scholar
  75. Puig, S. and Sorkin, L.S. Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 activity. Pain, 1996; 64:345–355.PubMedCrossRefGoogle Scholar
  76. Raja, S.N., Meyer, R.A. and Campbell, J.N. Peripheral mechanisms of somatic pain. Anesthesiology, 1988;68:571–590.PubMedCrossRefGoogle Scholar
  77. Randic, M., Hecimovic, H. and Ryu, P.D. Substance P modulates glutamate-induced currents in acutely isolated rat spinal dorsal horn neurones. Neuroscience Letters, 1990; 117:74–80.PubMedCrossRefGoogle Scholar
  78. Randic, M., Jiang, M.C. and Cerne, R. Long-term potentiation and long-term depression of primary afferent neurotransmission in the rat spinal cord. Journal of Neuroscience, 1993; 13:5228–524.PubMedGoogle Scholar
  79. Riedel, G., Wetzel, W. and Reymann, K.G. Comparing the role of metabotropic glutamate receptors in long-term potentiation and in learning and memory. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 1996; 20:761–789.PubMedCrossRefGoogle Scholar
  80. Sandkuhler, J. and Liu, X. Induction of long-term potentiation at spinal synapses by noxious stimulation or nerve injury. European Journal of Neuroscience, 1998; 10:2476–2480.PubMedCrossRefGoogle Scholar
  81. Simone, D.A., Baumann, T.K. and LaMotte, R.H. Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain, 1989; 38:99–107.PubMedCrossRefGoogle Scholar
  82. Simone, D.A., Ngeow, J.Y.F., Putterman, G.J. and LaMotte, R.H. Hyperalgesia to heat after intradermal injection of capsaicin. Brain Research, 1987; 418:201–203.PubMedCrossRefGoogle Scholar
  83. Simone, D.A., Nolano, M., Johnson, T., Wendelschafer-Crabb, G. and Kennedy, W.R. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. Journal of Neuroscience, 1998; 18:8947–8959.PubMedGoogle Scholar
  84. Simone, D.A., Sorkin, L.S., Oh, U., Chung, J.M., Owens, C., LaMotte, R.H. and Willis, W.D. Neurogenic hyperalgesia: central neural correlates in responses of spinothalamic tract neurons. Journal of Neurophysiology,61991; 6:228–246.Google Scholar
  85. Sluka, K.A. and Westlund, K.N. Centrally administered non-NMDA but not NMDA receptor antagonists block peripheral knee joint inflammation. Pain, 1993; 55:217–225.PubMedCrossRefGoogle Scholar
  86. Sluka, K.A. and Willis, W.D. The effects of G-protein and protein kinase inhibitors on the behavioral responses of rats to intradermal injection of capsaicin. Pain, 1997; 71:165–178.PubMedCrossRefGoogle Scholar
  87. Sluka, K.A. and Willis, W.D. Increased spinal release of excitatory amino acids following intradermal injection of capsaicin is reduced by a protein kinase G inhibitor. Brain Research, 1998; 798:281–286.PubMedCrossRefGoogle Scholar
  88. Sluka, K.A., Rees, H., Chen, P.S., Tsuruoka, M. and Willis, W.D. Inhibitors of G-proteins and protein kinases reduce the sensitization to mechanical stimulation and the desensitization to heat of spinothalamic tract neurons induced by intradermal injection of capsaicin in the primate. Experimental Brain Research, 1997a; 115:15–24.CrossRefGoogle Scholar
  89. Sluka, K.A., Rees, H., Chen, P.S., Tsuruoka, M. and Willis, W.D. Capsaicin-induced sensitization of primate spinothalamic tract cells is prevented by a protein kinase C inhibitor. Brain Research, 1997b; 772:82–86.CrossRefGoogle Scholar
  90. Sorkin, L.S. and McAdoo, D.J. Amino acids and serotonin are released into the lumbar spinal cord of the anesthetized cat following intradermal capsaicin injections. Brain Research, 1993; 607:89–98.PubMedCrossRefGoogle Scholar
  91. Svendsen, F., Tjølsen, A. and Hole, K. LTP of spinal Aß and C-fibre evoked responses after electrical sciatic nerve stimulation. Neuroreport, 1997; 8:3427–3430.PubMedCrossRefGoogle Scholar
  92. Thompson, R.F., Bao, S., Chen, L., Cipriano, B.D., Grethe, J.S., Kim, J.J., Thompson, J.K., Tracy, J.A., Weninger, M.S. and Krupa, D.J. Associative learning. International Review of Neurobiology, 1997;41:151–189.PubMedCrossRefGoogle Scholar
  93. Thompson, S.W.N., Gerber, G., Sivilotti, L.G. and Woolf, C.J. Long duration ventral root potentials in the neonatal rat spinal cord in vitro; the effects of ionotropic and metabotropic excitatory amino acid receptor antagonists. Brain Research, 1992; 595:87–97.PubMedCrossRefGoogle Scholar
  94. Thompson, S.W.N., Urban, L. and Dray, A. Contribution of NK1 and NK2 receptor activation to high threshold afferent fibre evoked ventral root responses in the rat spinal cord in vitro. Brain Research, 1993;625:100–108.PubMedCrossRefGoogle Scholar
  95. Tominaga, M., Caterina, M.J., Malmberg, A.B., Rosen, T.A., Gilbert, H., Skinner, K., Raumann, B.E., Basbaum, A.I. and Julius, D. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron, 1998; 21:531–543.PubMedCrossRefGoogle Scholar
  96. Torebjörk, H.E., Lundberg, L.E.R. and LaMotte, R.H. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. Journal of Physiology, 1992;448:765–780.PubMedGoogle Scholar
  97. Treede, R.D. and Cole, J.D. Dissociated secondary hyperalgesia in a subject with large-fibre sensory neuropathy. Pain, 1993; 53:169–174.PubMedCrossRefGoogle Scholar
  98. Vaello, M.L., Ruiz-Gómez, A., Lerma, J. and Mayor, F. Modulation of inhibitory glycine receptors by phosphorylation by protein kinase C and cAMP-dependent protein kinase. Journal of Biological Chemistry, 1994; 269:2002–2008.PubMedGoogle Scholar
  99. Willis, W.D. Mechanical allodynia. A role for sensitized nociceptive tract cells with convergent input from mechanoreceptors and nociceptors? APS Journal, 1993; 2:23–33.CrossRefGoogle Scholar
  100. Willis, W.D. Is central sensitization of nociceptive transmission in the spinal cord a variety of long-term potentiation? A commentary on the article by Svendsen, Tjelsen and Hole. In Focus, Neuroreport, 1997; 8:iii.PubMedGoogle Scholar
  101. Willis, W.D. Dorsal root potentials and dorsal root reflexes: a double-edged sword. Experimental Brain Research, 1999; 124:395–421.CrossRefGoogle Scholar
  102. Windhorst, U. The spinal cord and its brain: representations and models. To what extent do forebrain mechanisms appear at brainstem and spinal cord levels? Progress In Neurobiology, 1996; 49:381–414.PubMedCrossRefGoogle Scholar
  103. Woolf, C.J. Evidence for a central component of post-injury pain hypersensitivity. Nature, 1983; 306:686–688.PubMedCrossRefGoogle Scholar
  104. Woolf, C.J. (1992). Excitability changes in central neurons following peripheral damage: role of central sensitization in the pathogenesis of pain. In Willis, W.D. (Ed.), Hyperalgesia and Allodynia (pp. 221–243). New York: Raven Press.Google Scholar
  105. Woolf, C.J. Windup and central sensitization are not equivalent. Editorial. Pain, 1996; 66:105–108.Google Scholar
  106. Woolf, C.J. and King, A.E. Subthreshold components of the cutaneous mechanoreceptive fields of dorsal horn neurons in the rat lumbar spinal cord. Journal of Neurophysiology, 1989; 62:907–916.PubMedGoogle Scholar
  107. Woolf, C.J., Shortland, P. and Coggeshall, R.E. Peripheral nerve injury triggers central sprouting of myhelinated afferents. Nature, 1992; 355:75–78.PubMedCrossRefGoogle Scholar
  108. Wu, J., Fang, L., Lin, Q. and Willis, W.D. C-fos expression is induced by increased nitric oxide release in rat spinal cord dorsal horn. Neuroscience, 2000; 96:351–357.PubMedCrossRefGoogle Scholar
  109. Wu, J., Lin, Q. and Willis, W.D. Increased phosphorylation of cAMP-responsive element-binding protein (CREB) following nitric oxide release in rat spinal cord. Neuroscience Abstracts, 1999.Google Scholar
  110. Wu, J., Lin, Q., McAdoo, D.J. and Willis, W.D. Nitric oxide contributes to central sensitization following intradermal injection of capsaicin. Neuroreport, 1998; 9:589–592.PubMedCrossRefGoogle Scholar
  111. Yaksh, T.L. Behavioral and autonomic correlates of tactile evoked allodynia produced by spinal glycine inhibition: effects of modulatory receptor systems and excitatory amino acid antagonists. Pain, 1989; 37:111–123.PubMedCrossRefGoogle Scholar
  112. Yoon, Y.W., Na, H.S. and Chung, J.M. Contributions of injured and intact afferents to neuropathic pain in an experimental rat model. Pain, 1996; 64:27–36.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • William D. WillisJr.
    • 1
  1. 1.Department of Anatomy and Neurosciences and Marine Biomedical InstituteUniversity of Texas Medical BranchGalvestonUSA

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