ATP Receptors in the Pain Signaling: Glial Contribution in Neuropathic Pain

  • Kazuhide Inoue

There is abundant evidence that extracellular ATP has an important role in pain signaling at both the periphery and in the CNS. The focus of attention now is on the possibility that ATP and its receptor system might play important roles in chronic pathological pain states, particularly in neuropathic pain. Neuropathic pain is often a consequence of nerve injury through surgery, bone compression, diabetes, or infection. This type of pain can be so severe that even light touching can be intensely painful. Unfortunately, this state is generally resistant to currently available treatments. In this review, we summarize the role of ATP receptor P2X4 and P2X7 in spinal microglia in neuropathic pain. The activated microglia express P2X4 after nerve injury, which can be stimulated by endogenous ATP, resulting in the release of brain-derived neurotrophic factor that is one of key molecules involving in neuropathic pain. The stimulation of microglial P2X7 releases cytokines including TNF-α and IL- 1β. Understanding the key roles of these ATP receptors may lead to new strategies for the management of intractable chronic pain.


Neuropathic Pain Nerve Injury Dorsal Horn Mechanical Allodynia Peripheral Nerve Injury 
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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9. References

  1. Barclay, J., Patel, S., Dorn, G., Wotherspoon, G., Moffatt, S., Eunson, L., Abdel’al, S., Natt, F., Hall, J., Winter, J., Bevan, S., Wishart, W., Fox, A. and Ganju, P., 2002, Functional downregulation of P2X3 receptor subunit in rat sensory neurons reveals a significant role in chronic neuropathic and inflammatory pain. J. Neurosci. 22: 8139.PubMedGoogle Scholar
  2. Bennett, G.J. and Xie, Y.K., 1988, A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33: 87.PubMedGoogle Scholar
  3. Bland-Ward, P.A. and Humphrey, P.P., 1997, Acute nociception mediated by hindpaw P2X receptor activation in the rat. Br. J. Pharmacol. 122: 365.PubMedGoogle Scholar
  4. Bleehen, T. and Keele, C.A., 1977, Observations on the algogenic actions of adenosine compounds on the human blister base preparation. Pain 3: 367.PubMedGoogle Scholar
  5. Bleehen, T., Hobbiger, F. and Keele, C.A., 1976, Identification of algogenic substances in human erythrocytes. J. Physiol. 262: 131.PubMedGoogle Scholar
  6. Burnstock, G., 2000, P2X receptors in sensory neurones. Br. J. Anaesth. 84: 476.PubMedGoogle Scholar
  7. Burnstock, G. and Wood, J.N., 1996, Purinergic receptors: their role in nociception and primary afferent neurotransmission. Curr. Opin. Neurobiol. 6: 526.PubMedGoogle Scholar
  8. Casula, M.A., Facer, P., Powell, A.J., Kinghorn, I.J., Plumpton, C., Tate, S.N., Bountra, C., Birch, R. and Anand, P., 2004, Expression of the sodium channel beta3 subunit in injured human sensory neurons. Neuroreport 15: 1629.PubMedGoogle Scholar
  9. Chen, C.C., Akopian, A.N., Sivilotti, L., Colquhoun, D., Burnstock, G. and Wood, J.N., 1995, A P2X purinoceptor expressed by a subset of sensory neurons. Nature 377: 428.PubMedGoogle Scholar
  10. Chessell, I.P., Hatcher, J.P., Bountra, C., Michel, A.D., Hughes, J.P., Green, P., Egerton, J., Murfin, M., Richardson, J., Peck, W.L., Grahames, C.B., Casula, M.A., Yiangou, Y., Birch, R., Anand, P. and Buell, G.N., 2005, Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114: 386.PubMedGoogle Scholar
  11. Chizh, B.A. and Illes, P., 2001, P2X receptors and nociception. Pharmacol. Rev. 53: 553.PubMedGoogle Scholar
  12. Cockayne, D.A., Hamilton, S.G., Zhu, Q.M., Dunn, P.M., Zhong, Y., Novakovic, S., Malmberg, A.B., Cain, G., Berson, A., Kassotakis, L., Hedley, L., Lachnit, W.G., Burnstock, G., McMahon, S.B. and Ford, A.P., 2000, Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407: 1011.PubMedGoogle Scholar
  13. Colburn, R.W., DeLeo, J.A., Rickman, A.J., Yeager, M.P., Kwon, P. and Hickey, W.F., 1997, Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J. Neuro-immunol. 79: 163.Google Scholar
  14. Colburn, R.W., Rickman, A.J. and DeLeo, J.A., 1999, The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp. Neurol. 157: 289.PubMedGoogle Scholar
  15. Cook, S.P., Rodland, K.D. and McCleskey, E.W., 1998, A memory for extracellular Ca2+ by speeding recovery of P2X receptors from desensitization. J. Neurosci. 18: 9238.PubMedGoogle Scholar
  16. Coull, J.A., Boudreau, D., Bachand, K., Prescott, S.A., Nault, F., Sik, A., De Koninck, P. and De Koninck, Y., 2003, Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424: 938.PubMedGoogle Scholar
  17. Coull, J.A., Beggs, S., Boudreau, D., Boivin, D., Tsuda, M., Inoue, K., Gravel, C., Salter, M.W. and De Koninck, Y., 2005, BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438: 1017.PubMedGoogle Scholar
  18. Coyle, D.E., 1998, Partial peripheral nerve injury leads to activation of astroglia and microglia which parallels the development of allodynic behavior. Glia 23: 75.PubMedGoogle Scholar
  19. Dai, Y., Fukuoka, T., Wang, H., Yamanaka, H., Obata, K., Tokunaga, A. and Noguchi, K., 2004, Contribution of sensitized P2X receptors in inflamed tissue to the mechanical hypersensitivity revealed by phosphorylated ERK in DRG neurons. Pain 108: 258.PubMedGoogle Scholar
  20. Decosterd, I. and Woolf, C.J., 2000, Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87: 149.PubMedGoogle Scholar
  21. DeLeo, J.A. and Yezierski, R.P., 2001, The role of neuroinflammation and neuroimmune activation in persistent pain. Pain 90: 1.PubMedGoogle Scholar
  22. Diem, R., Meyer, R., Weishaupt, J.H. and Bahr, M., 2001, Reduction of potassium currents and phosphatidylinositol 3-kinase-dependent AKT phosphorylation by tumor necrosis factor-(alpha) rescues axotomized retinal ganglion cells from retrograde cell death in vivo. J. Neurosci. 21: 2058.PubMedGoogle Scholar
  23. Dorn, G., Abdel’Al, S., Natt, F.J., Weiler, J., Hall, J., Meigel, I., Mosbacher, J. and Wishart, W., 2001, Specific inhibition of the rat ligand-gated ion channel P2X3 function via methoxyethoxy-modified phosphorothioated antisense oligonucleotides. Antisense Nucleic Acid Drug Dev. 11: 165.PubMedGoogle Scholar
  24. Dunn, P.M., Zhong, Y. and Burnstock, G., 2001, P2X receptors in peripheral neurons. Prog. Neurobiol. 65: 107.PubMedGoogle Scholar
  25. Eriksson, N.P., Persson, J.K., Svensson, M., Arvidsson, J., Molander, C. and Aldskogius, H., 1993, A quantitative analysis of the microglial cell reaction in central primary sensory projection territories following peripheral nerve injury in the adult rat. Exp. Brain Res. 96: 19.PubMedGoogle Scholar
  26. Ferrari, D., Villalba, M., Chiozzi, P., Falzoni, S., Ricciardi-Castagnoli, P. and Di Virgilio, F., 1996, Mouse microglial cells express a plasma membrane pore gated by extracellular ATP. J. Immunol. 156: 1531.PubMedGoogle Scholar
  27. Ferrari, D., Chiozzi, P., Falzoni, S., Hanau, S., and Di Virgilio, F., 1997, Purinergic modulation of interleukin-1 beta release from microglial cells stimulated with bacterial endotoxin. J. Exp. Med. 185: 579.PubMedGoogle Scholar
  28. Furukawa, K. and Mattson, M.P., 1998, The transcription factor NF-kappaB mediates increases in calcium currents and decreases in NMDA- and AMPA/kainate-induced currents induced by tumor necrosis factor-alpha in hippocampal neurons. J. Neurochem. 70: 1876.PubMedGoogle Scholar
  29. Gehrmann, J. and Banati, R.B., 1995, Microglial turnover in the injured CNS: activated microglia undergo delayed DNA fragmentation following peripheral nerve injury. J. Neuropathol. Exp. Neurol. 54: 680.PubMedGoogle Scholar
  30. Gravel, C., Gotz, R., Lorrain, A. and Sendtner, M., 1997, Adenoviral gene transfer of ciliary neurotrophic factor and brain-derived neurotrophic factor leads to long-term survival of axotomized motor neurons. Nat. Med. 3: 765.PubMedGoogle Scholar
  31. Hamilton, S.G., Wade, A. and McMahon, S.B., 1999, The effects of inflammation and inflammatory mediators on nociceptive behaviour induced by ATP analogues in the rat. Br. J. Pharmacol. 126: 326.PubMedGoogle Scholar
  32. Hashizume, H., DeLeo, J.A., Colburn, R.W. and Weinstein, J.N., 2000, Spinal glial activation and cytokine expression after lumbar root injury in the rat. Spine 25: 1206.PubMedGoogle Scholar
  33. Heppenstall, P.A. and Lewin, G.R., 2001, BDNF but not NT-4 is required for normal flexion reflex plasticity and function. Proc. Natl. Acad. Sci. USA 98: 8107.PubMedGoogle Scholar
  34. Hide, I., Tanaka, M., Inoue, A., Nakajima, K., Kohsaka, S., Inoue, K. and Nakata, Y., 2000, Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia. J. Neurochem. 75: 965.PubMedGoogle Scholar
  35. Homma, Y., Brull, S.J. and Zhang, J.M., 2002, A comparison of chronic pain behavior following local application of tumor necrosis factor alpha to the normal and mechanically compressed lumbar ganglia in the rat. Pain 95: 239.PubMedGoogle Scholar
  36. Jarvis, M.F., Burgard, E.C., McGaraughty, S., Honore, P., Lynch, K., Brennan, T.J., Subieta, A., Van Biesen, T., Cartmell, J., Bianchi, B., Niforatos, W., Kage, K., Yu, H., Mikusa, J., Wismer, C.T., Zhu, C.Z., Chu, K., Lee, C.H., Stewart, A.O., Polakowski, J., Cox, B.F., Kowaluk, E., Williams, M., Sullivan, J. and Faltynek, C., 2002, A-317491, a novel potent and selective non-nucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat. Proc. Natl. Acad. Sci. USA 99: 17179.PubMedGoogle Scholar
  37. Ji, R.R., Samad, T.A., Jin, S.X., Schmoll, R. and Woolf, C.J., 2002, P38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36: 57.PubMedGoogle Scholar
  38. Jin, S.X., Zhuang, Z.Y., Woolf, C.J. and Ji, R.R., 2003, 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: 4017.PubMedGoogle Scholar
  39. Junger, H. and Sorkin, L.S., 2000, Nociceptive and inflammatory effects of subcutaneous TNFalpha. Pain 85: 145.PubMedGoogle Scholar
  40. Kennedy, C., Assis, T.S., Currie, A.J. and Rowan, E.G., 2003, Crossing the pain barrier: P2 receptors as targets for novel analgesics. J. Physiol. 553: 683.PubMedGoogle Scholar
  41. Kerr, B.J., Bradbury, E.J., Bennett, D.L., Trivedi, P.M., Dassan, P., French, J., Shelton, D.B., McMahon, S.B. and Thompson, S.W., 1999, Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord. J. Neurosci. 19: 5138.PubMedGoogle Scholar
  42. Khakh, B.S., Burnstock, G., Kennedy, C., King, B.F., North, R.A., Seguela, P., Voigt, M. and Humphrey, P.P., 2001, International union of pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits. Pharmacol. Rev. 53: 107.PubMedGoogle Scholar
  43. Kim, S.H. and Chung, J.M., 1992, An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50: 355.PubMedGoogle Scholar
  44. Koizumi, S., Tsuda, M., Shigemoto, Y., Obama, T. and Inoue, K., 2001, Characterization of P2Y receptors in cultured rat dorsal root ganglion neurons. Jpn. J. Pharmacol. 85: 149P.Google Scholar
  45. Kreutzberg, G.W., 1996, Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19: 312.PubMedGoogle Scholar
  46. Leem, J.G. and Bove, G.M., 2002, Mid-axonal tumor necrosis factor-alpha induces ectopic activity in a subset of slowly conducting cutaneous and deep afferent neurons. J. Pain 3: 45.PubMedGoogle Scholar
  47. Lewis, C., Neidhart, S., Holy, C., North, R.A., Buell, G. and Surprenant, A., 1995, Coexpression of P2X2 and P2X3 receptor subunits can account for ATP- gated currents in sensory neurons. Nature 377: 432.PubMedGoogle Scholar
  48. Li, C., Peoples, R.W., Lanthorn, T.H., Li, Z.W. and Weight, F.F., 1999, Distinct ATP-activated currents in different types of neurons dissociated from rat dorsal root ganglion. Neurosci. Lett. 263: 57.PubMedGoogle Scholar
  49. Liu, L., Tornqvist, E., Mattsson, P., Eriksson, N.P., Persson, J.K., Morgan, B.P., Aldskogius, H. and Svensson, M., 1995, Complement and clusterin in the spinal cord dorsal horn and gracile nucleus following sciatic nerve injury in the adult rat. Neuroscience 68: 167.PubMedGoogle Scholar
  50. Mannion, R.J., Costigan, M., Decosterd, I., Amaya, F., Ma, Q.P., Holstege, J.C., Ji, R.R., Acheson, A., Lindsay, R.M., Wilkinson, G.A. and Woolf, C.J., 1999, Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. Proc. Natl. Acad. Sci. USA 96: 9385.PubMedGoogle Scholar
  51. Molliver, D.C., Cook, S.P., Carlsten, J.A., Wright, D.E. and McCleskey, E.W., 2002, ATP and UTP excite sensory neurons and induce CREB phosphorylation through the metabotropic receptor, P2Y2. Eur. J. Neurosci. 16: 1850.Google Scholar
  52. Moriyama, T., Iida, T., Kobayashi, K., Higashi, T., Fukuoka, T., Tsumura, H., Leon, C., Suzuki, N., Inoue, K., Gachet, C., Noguchi, K. and Tominaga, M., 2003, Possible involvement of P2Y2 metabotropic receptors in ATP-induced transient receptor potential vanilloid receptor 1-mediated thermal hypersensitivity. J. Neurosci. 23: 6058.PubMedGoogle Scholar
  53. Onda, A., Murata, Y., Rydevik, B., Larsson, K., Kikuchi, S. and Olmarker, K., 2004, Infliximab attenuates immunoreactivity of brain-derived neurotrophic factor in a rat model of herniated nucleus pulposus. Spine 29: 1857.PubMedGoogle Scholar
  54. Perregaux, D. and Gabel, C.A., 1994, Interleukin-1 beta maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity. J. Biol. Chem. 269: 15195.PubMedGoogle Scholar
  55. Perry, V.H., 1994, Modulation of microglia phenotype. Neuropathol. Appl. Neurobiol. 20: 177.PubMedGoogle Scholar
  56. Pollock, J., McFarlane, S.M., Connell, M.C., Zehavi, U., Vandenabeele, P., MacEwan, D.J. and Scott, R.H., 2002, TNF-alpha receptors simultaneously activate Ca2+ mobilisation and stress kinases in cultured sensory neurones. Neuropharmacology 42: 93.PubMedGoogle Scholar
  57. Raghavendra, V., Tanga, F. and DeLeo, J.A., 2003, Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J. Pharmacol. Exp. Ther. 306: 624.PubMedGoogle Scholar
  58. Ralevic, V. and Burnstock, G., 1998, Receptors for purines and pyrimidines. Pharmacol. Rev. 50: 413.PubMedGoogle Scholar
  59. Rivera, C., Li, H., Thomas-Crusells, J., Lahtinen, H., Viitanen, T., Nanobashvili, A., Kokaia, Z., Airaksinen, M.S., Voipio, J., Kaila, K. and Saarma, M., 2002, BDNF-induced TrkB activation down-regulates the K+-Cl cotransporter KCC2 and impairs neuronal Cl- extrusion. J. Cell Biol. 159: 747.PubMedGoogle Scholar
  60. Robertson, B., Xu, X.J., Hao, J.X., Wiesenfeld-Hallin, Z., Mhlanga, J., Grant, G. and Kristensson, K., 1997, Interferon-gamma receptors in nociceptive pathways: role in neuropathic pain-related behaviour. Neuroreport 8: 1311.PubMedGoogle Scholar
  61. Sanada, M., Yasuda, H., Omatsu-Kanbe, M., Sango, K., Isono, T., Matsuura, H. and Kikkawa, R., 2002, Increase in intracellular Ca(2+) and calcitonin gene-related peptide release through metabotropic P2Y receptors in rat dorsal root ganglion neurons. Neuroscience 111: 413.PubMedGoogle Scholar
  62. Sanz, J.M. and Di Virgilio, F., 2000, Kinetics and mechanism of ATP-dependent IL-1 beta release from microglial cells. J. Immunol. 164: 4893.PubMedGoogle Scholar
  63. Sawada, M., Hara, N. and Maeno, T., 1990, Extracellular tumor necrosis factor induces a decreased K+ conductance in an identified neuron of Aplysia kurodai. Neurosci. Lett. 115: 219.PubMedGoogle Scholar
  64. Schafers, M., Geis, C., Brors, D., Yaksh, T.L. and Sommer, C., 2002, Anterograde transport of tumor necrosis factor-alpha in the intact and injured rat sciatic nerve. J. Neurosci. 22: 536.PubMedGoogle Scholar
  65. Schafers, M., Lee, D.H., Brors, D., Yaksh, T.L. and Sorkin, L.S., 2003a, Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation. J. Neurosci. 23: 3028.PubMedGoogle Scholar
  66. Schafers, M., Svensson, C.I., Sommer, C. and Sorkin, L.S., 2003b, Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J. Neurosci. 23: 2517.PubMedGoogle Scholar
  67. Scholz, J. and Woolf, C.J., 2002, Can we conquer pain? Nat. Neurosci. 5 suppl.: 1062.PubMedGoogle Scholar
  68. Seltzer, Z., Dubner, R. and Shir, Y., 1990, A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 43: 205.PubMedGoogle Scholar
  69. Soliven, B. and Albert, J., 1992, Tumor necrosis factor modulates Ca2+ currents in cultured sympathetic neurons. J. Neurosci. 12: 2665.PubMedGoogle Scholar
  70. Sommer, C. and Schafers, M., 1998, Painful mononeuropathy in C57BL/Wld mice with delayed wallerian degeneration: differential effects of cytokine production and nerve regeneration on thermal and mechanical hypersensitivity. Brain Res. 784: 154.PubMedGoogle Scholar
  71. Sommer, C., Marziniak, M. and Myers, R.R., 1998, The effect of thalidomide treatment on vascular pathology and hyperalgesia caused by chronic constriction injury of rat nerve. Pain 74: 83.PubMedGoogle Scholar
  72. Sommer, C., Schafers, M., Marziniak, M. and Toyka, K.V., 2001a, Etanercept reduces hyperalgesia in experimental painful neuropathy. J. Peripher. Nerv. Syst. 6: 67.PubMedGoogle Scholar
  73. Sommer, C., Lindenlaub, T., Teuteberg, P., Schafers, M., Hartung, T. and Toyka, K.V., 2001b, Anti-TNF-neutralizing antibodies reduce pain-related behavior in two different mouse models of painful mononeuropathy. Brain Res. 913: 86.PubMedGoogle Scholar
  74. Sorkin, L.S. and Doom, C.M., 2000, Epineurial application of TNF elicits an acute mechanical hyperalgesia in the awake rat. J. Peripher. Nerv. Syst. 5: 96.PubMedGoogle Scholar
  75. Sorkin, L.S., Xiao, W.H., Wagner, R. and Myers, R.R., 1997, Tumour necrosis factor-alpha induces ectopic activity in nociceptive primary afferent fibres. Neuroscience 81: 255.PubMedGoogle Scholar
  76. Souslova, V., Cesare, P., Ding, Y., Akopian, A.N., Stanfa, L., Suzuki, R., Carpenter, K., Dickenson, A., Boyce, S., Hill, R., Nebenuis-Oosthuizen, D., Smith, A.J., Kidd, E.J. and Wood, J.N., 2000, Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature 407: 1015.PubMedGoogle Scholar
  77. Stoll, G. and Jander, S., 1999, The role of microglia and macrophages in the pathophysiology of the CNS. Prog. Neurobiol. 58: 233.PubMedGoogle Scholar
  78. Stuesse, S.L., Cruce, W.L., Lovell, J.A., McBurney, D.L. and Crisp, T., 2000, Microglial proliferation in the spinal cord of aged rats with a sciatic nerve injury. Neurosci. Lett. 287: 121.PubMedGoogle Scholar
  79. Surprenant, A., Rassendren, F., Kawashima, E., North, R.A. and Buell, G., 1996, The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science 272: 735.PubMedGoogle Scholar
  80. Suzuki, T., Hide, I., Ido, K., Kohsaka, S., Inoue, K. and Nakata, Y., 2004, Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia. J. Neurosci. 24: 1.PubMedGoogle Scholar
  81. Svichar, N., Shmigol, A., Verkhratsky, A. and Kostyuk, P., 1997, ATP induces Ca2+ release from IP3-sensitive Ca2+ stores exclusively in large DRG neurones. Neuroreport 8: 1555.PubMedGoogle Scholar
  82. Sweitzer, S., Martin, D. and DeLeo, J.A., 2001, 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: 529.PubMedGoogle Scholar
  83. Thompson, S.W., Bennett, D.L., Kerr, B.J., Bradbury, E.J. and McMahon, S.B., 1999, Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord. Proc. Natl. Acad. Sci. USA 96: 7714.PubMedGoogle Scholar
  84. Tominaga, M., Wada, M. and Masu, M., 2001, Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia. Proc. Natl. Acad. Sci. USA 98: 6951.PubMedGoogle Scholar
  85. Tsuda, M., Ueno, S. and Inoue, K., 1999, In vivo pathway of thermal hyperalgesia by intrathecal administration of alpha,beta-methylene ATP in mouse spinal cord: involvement of the glutamate-NMDA receptor system. Br. J. Pharmacol. 127: 449.PubMedGoogle Scholar
  86. Tsuda, M., Koizumi, S., Kita, A., Shigemoto, Y., Ueno, S. and Inoue, K., 2000, Mechanical allodynia caused by intraplantar injection of P2X receptor agonist in rats: involvement of heteromeric P2X2/3 receptor signaling in capsaicin-insensitive primary afferent neurons. J. Neurosci. 20: RC90.Google Scholar
  87. Tsuda, M., Shigemoto-Mogami, Y., Ueno, S., Koizumi, S., Ueda, H., Iwanaga, T. and Inoue, K., 2002, Downregulation of P2X3 receptor-dependent sensory functions in A/J inbred mouse strain. Eur. J. Neurosci. 15: 1444.PubMedGoogle Scholar
  88. Tsuda, M., Shigemoto-Mogami, Y., Koizumi, S., Mizokoshi, A., Kohsaka, S., Salter, M.W. and Inoue, K., 2003, P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424: 778.PubMedGoogle Scholar
  89. Tsuda, M., Mizokoshi, A., Shigemoto-Mogami, Y., Koizumi, S. and Inoue, K., 2004, Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia 45: 89.PubMedGoogle Scholar
  90. Tsuzuki, K., Kondo, E., Fukuoka, T., Yi, D., Tsujino, H., Sakagami, M. and Noguchi, K., 2001, Differential regulation of P2X(3) mRNA expression by peripheral nerve injury in intact and injured neurons in the rat sensory ganglia. Pain 91: 351.PubMedGoogle Scholar
  91. Ueno, S., Tsuda, M., Iwanaga, T. and Inoue, K., 1999, Cell type-specific ATP-activated responses in rat dorsal root ganglion neurons. Br. J. Pharmacol. 126: 429.PubMedGoogle Scholar
  92. Vikman, K.S., Hill, R.H., Backstrom, E., Robertson, B. and Kristensson, K., 2003, Interferon-gamma induces characteristics of central sensitization in spinal dorsal horn neurons in vitro. Pain 106: 241.PubMedGoogle Scholar
  93. Virginio, C., Robertson, G., Surprenant, A. and North, R.A., 1998, Trinitrophenyl-substituted nucleotides are potent antagonists selective for P2X1, P2X3, and heteromeric P2X2/3 receptors. Mol. Pharmacol. 53: 969.PubMedGoogle Scholar
  94. Viviani, B., Bartesaghi, S., Gardoni, F., Vezzani, A., Behrens, M.M., Bartfai, T., Binaglia, M., Corsini, E., Di Luca, M., Galli, C.L. and Marinovich, M., 2003, Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J. Neurosci. 23: 8692.PubMedGoogle Scholar
  95. Wagner, R. and Myers, R.R., 1996, Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. Neuroreport 7: 2897.PubMedGoogle Scholar
  96. Wall, P.D., Devor, M., Inbal, R., Scadding, J.W., Schonfeld, D., Seltzer, Z. and Tomkiewicz, M.M., 1979, Autotomy following peripheral nerve lesions: experimental anaesthesia dolorosa. Pain 7: 103.PubMedGoogle Scholar
  97. Wang, S., Cheng, Q., Malik, S. and Yang, J., 2000, Interleukin-1beta inhibits gamma-aminobutyric acid type A (GABA(A)) receptor current in cultured hippocampal neurons. J. Pharmacol. Exp. Ther. 292: 497.PubMedGoogle Scholar
  98. Watkins, L.R. and Maier, S.F., 2003, GLIA: A novel drug discovery target for clinical pain. Nat. Rev. Drug Discov. 2: 973.PubMedGoogle Scholar
  99. Watkins, L.R., Milligan, E.D. and Maier, S.F., 2001, Spinal cord glia: new players in pain. Pain 93: 201.PubMedGoogle Scholar
  100. Winkelstein, B.A., Rutkowski, M.D., Sweitzer, S.M., Pahl, J.L. and DeLeo, J.A., 2001, Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment. J. Comp. Neurol. 439: 127.PubMedGoogle Scholar
  101. Woolf, C.J. and Mannion, R.J., 1999, Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353: 1959.PubMedGoogle Scholar
  102. Woolf, C.J. and Salter, M.W., 2000, Neuronal plasticity: increasing the gain in pain. Science 288: 1765.PubMedGoogle Scholar
  103. Yu, X.M., Askalan, R. and Keil, G.J. 2nd and Salter, M.W., 1997, NMDA channel regulation by channel-associated protein tyrosine kinase Src. Science 275: 674.PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Kazuhide Inoue
    • 1
  1. 1.Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical SciencesKyushu UniversityJapan

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