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Contribution of the spared primary afferent neurons to the pathomechanisms of neuropathic pain

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Abstract

Neuropathic pain is caused by nervous-system lesions. Early studies on the pathomechanisms of this abnormal pain state have focused on the directly injured fibers and neurons. Here, we present recently accumulating data about the contribution of the primary afferent neurons spared from direct injury to the pathomechanisms of neuropathic pain. The phenotypic changes in the spared neurons are similar to those in the neurons in peripheral inflammation models, as opposed to those in the directly injured neurons. Electrophysiological changes and behavioral data also favor the contribution of the spared neurons. These attractive targets of study will give us new approaches for understanding the abnormal pain.

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References

  1. Neumann S., Doubell T. P., Leslie T. and Woolf C. J. (1996) Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons. Nature 384, 360–364.

    Article  PubMed  CAS  Google Scholar 

  2. Mannion R. J., Costigan M., Decosterd I., Amaya F., Ma Q. P., Holstege J. C., et al. (1999) Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. Proc. Natl. Acad. Sci. USA 96, 9385–9390.

    Article  PubMed  CAS  Google Scholar 

  3. 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, 87–107.

    Article  PubMed  CAS  Google Scholar 

  4. 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, 205–218.

    Article  PubMed  CAS  Google Scholar 

  5. 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, 355–363.

    Article  PubMed  CAS  Google Scholar 

  6. Decosterd I. and Woolf C. J. (2000) Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87, 149–158.

    Article  PubMed  CAS  Google Scholar 

  7. Takahashi Y., Nakajima Y. and Sakamoto T. (1994) Dermatome mapping in the hindlimb by electrical stimulation of the spinal nerves. Neurosci. Lett. 168, 85–88.

    Article  PubMed  CAS  Google Scholar 

  8. Boucher T. J., Okuse K., Bennett D. L., Munson J. B., Wood J. N. and McMahon S. B. (2000) Potent analgesic effects of GDNF in neuropathic pain states. Science 290, 124–127.

    Article  PubMed  CAS  Google Scholar 

  9. Liu X., Eschenfelder S., Blenk K. H., Janig W. and Habler H. (2000) Spontaneous activity of axotomized afferent neurons after L5 spinal nerve injury in rats. Pain 84, 309–318.

    Article  PubMed  CAS  Google Scholar 

  10. Donnerer J., Schuligoi R. and Stein C. (1992) Increased content and transport of substance P and calcitonin gene- related peptide in sensory nerves innervating inflammed tissue: evidence for a regulatory function of nerve growth factor in vivo. Neuroscience 49, 693–698.

    Article  PubMed  CAS  Google Scholar 

  11. Ma W. and Bisby M. A. (1998) Increase of preprotachykinin mRNA and substance P immunoreactivity in spared dorsal root ganglion neurons following partial sciatic nerve injury. Eur. J. Neurosci. 10, 2388–2399.

    Article  PubMed  CAS  Google Scholar 

  12. Fukuoka T., Tokunaga A., Kondo E. and Noguchi K. (2000) The role of neighboring intact dorsal root ganglion neurons in a rat neuropathic pain model, in Progress in Pain Research and Management, vol. 16 (Wiesenfeld-Hallin Z., ed), IASP Press, Seattle, WA, pp. 137–146.

    Google Scholar 

  13. Fukuoka T., Tokunaga A., Kondo E., Miki K., Tachibana T. and Noguchi K. (1998) Change in mRNAs for neuropeptides and the GABA(A) receptor in dorsal root ganglion neurons in a rat experimental neuropathic pain model. Pain 78, 13–26.

    Article  PubMed  CAS  Google Scholar 

  14. Julius D. and Basbaum A. I. (2001) Molecular mechanisms of nociception. Nature 413, 203–210.

    Article  PubMed  CAS  Google Scholar 

  15. Miletic V. and Tan H. (1988) Iontophoretic application of calcitonin gene-related peptide produces a slow and prolonged excitation of neurons in the cat lumbar dorsal horn. Brain Res. 446, 169–172.

    Article  PubMed  CAS  Google Scholar 

  16. Ryu P. D., Gerber G., Murase K. and Randic M. (1988) Actions of calcitonin generelated peptide on rat spinal dorsal horn neurons. Brain Res. 441, 357–361.

    Article  PubMed  CAS  Google Scholar 

  17. Woolf C. J. and Salter M. W. (2000) Neuronal plasticity: increasing the gain in pain. Science. 288, 1765–1769.

    Article  PubMed  CAS  Google Scholar 

  18. Quirion R., Van Rossum D., Dumont Y., St-Pierre S. and Fournier A. (1992) Characterization of CGRP1 and CGRP2 receptor subtypes. Ann. NY Acad. Sci. 657, 88–105.

    Article  PubMed  CAS  Google Scholar 

  19. Aiyar N., Rand K., Elshourbagy N. A., Zeng Z., Adamou J. E., Bergsma D. J. and Li Y. (1996) A cDNA encoding the calcitonin gene-related peptide type 1 receptor. J. Biol. Chem. 271, 11325–11329.

    Article  PubMed  CAS  Google Scholar 

  20. McLatchie L. M., Fraser N. J., Main M. J., Wise A., Brown J., Thompson N., et al. (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393, 333–339.

    Article  PubMed  CAS  Google Scholar 

  21. Evans B. N., Rosenblatt M. I., Mnayer L. O., Oliver K. R. and Dickerson I. M. (2000) CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors. J. Biol. Chem. 275, 31438–31443.

    Article  PubMed  CAS  Google Scholar 

  22. Ryu P. D., Gerber G., Murase K. and Randic M. (1988) Calcitonin gene-related peptide enhances calcium current of rat dorsal root ganglion neurons and spinal excitatory synaptic transmission. Neurosci. Lett. 89, 305–312.

    Article  PubMed  CAS  Google Scholar 

  23. Li H. S. and Zhao Z. Q. (1998) Small sensory neurons in the rat dorsal root ganglia express functional NK-1 tachykinin receptor. Eur. J. Neurosci. 10, 1292–1299.

    Article  PubMed  CAS  Google Scholar 

  24. Cho H. J., Kim S. Y., Park M. J., Kim D. S., Kim J. K. and Chu M. Y. (1997) Expression of mRNA for brain-derived neurotrophic factor in the dorsal root ganglion following peripheral inflammation. Brain Res. 749, 358–362.

    Article  PubMed  CAS  Google Scholar 

  25. Kashiba H., Ueda Y., Ueyama T., Nemoto K. and Senba E. (1997) Relationship between BDNF- and trk-expressing neurones in rat dorsal root ganglion: an analysis by in situ hybridization. Neuroreport 8, 1229–1234.

    Article  PubMed  CAS  Google Scholar 

  26. Michael G. J., Averill S., Nitkunan A., Rattray M., Bennett D. L., Yan Q. and Priestley J. V. (1997) Nerve growth factor treatment increases brain-derived neurotrophic factor selectivity in TrkA-expressing dorsal root ganglion cells and in their central terminations within the spinal cord. J. Neurosci. 17, 8476–8490.

    PubMed  CAS  Google Scholar 

  27. Cho H. J., Kim J. K., Park H. C., Kim J. K., Kim D. S., Ha S. O. and Hong H. S. (1998) Changes in brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia, spinal cord, and gracile nuclei following cut or crush injuries. Exp. Neurol. 154, 224–230.

    Article  PubMed  CAS  Google Scholar 

  28. Michael G. J., Averill S., Shortland P. J., Yan Q. and Priestley J. V. (1999) Axotomy results in major changes in BDNF expression by dorsal root ganglion cells: BDNF expression in large trkB and trkC cells, in pericellular baskets, and in projections to deep dorsal horn and dorsal column nuclei. Eur. J. Neurosci. 11, 3539–3551.

    Article  PubMed  CAS  Google Scholar 

  29. Fukuoka T., Kondo E., Dai Y., Hashimoto N. and Noguchi K. (2001) Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model. J. Neurosci. 21, 4891–4900.

    PubMed  CAS  Google Scholar 

  30. Ha S. O., Kim J. K., Hong H. S., Kim D. S. and Cho H. J. (2001) Expression of brain-derived neurotrophic factor in rat dorsal root ganglia, spinal cord and gracile nuclei in experimental models of neuropathic pain. Neuroscience 107, 301–309.

    Article  PubMed  CAS  Google Scholar 

  31. Zhou X. F. and Rush R. A. (1996) Endogenous brain-derived neurotrophic factor is anterogradely transported in primary sensory neurons. Neuroscience 74, 945–953.

    PubMed  CAS  Google Scholar 

  32. Suen P. C., Wu K., Levine E. S., Mount H. T., Xu J. L., Lin S. Y. and Black I. B. (1997) Brain-derived neurotrophic factor rapidly enhances phosphorylation of the postsynaptic N-methyl-D-aspartate receptor subunit 1. Proc. Natl. Acad. Sci. USA 94, 8191–8195.

    Article  PubMed  CAS  Google Scholar 

  33. McMahon S. B., Armanini M. P., Ling L. H. and Phillips H. S. (1994) Expression and coexpression of Trk receptors in subpopulations of adult primary sensory neurons projecting to identified peripheral targets. Neuron 12, 1161–1171.

    Article  PubMed  CAS  Google Scholar 

  34. Shu X. Q., Llinas A. and Mendell L. M. (1999) Effects of trkB and trkC neurotrophin receptor agonists on thermal nociception: a behavioral and electrophysiological study. Pain 80, 463–470.

    Article  PubMed  CAS  Google Scholar 

  35. Zhou X. F., Deng Y. S., Xian C. J. and Zhong J. H. (2000) Neurotrophins from dorsal root ganglia trigger allodynia after spinal nerve injury in rats. Eur. J. Neurosci. 12, 100–105.

    Article  PubMed  CAS  Google Scholar 

  36. Caterina M. J., Rosen T. A., Tominaga M., Brake A. J. and Julius D. (1999) A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398, 436–441.

    Article  PubMed  CAS  Google Scholar 

  37. Caterina M. J., Leffler A., Malmberg A. B., Martin W. J., Trafton J., Petersen Z. K., et al. (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor [see comments]. Science 288, 306–313.

    Article  PubMed  CAS  Google Scholar 

  38. Guo A., Vulchanova L., Wang J., Li X. and Elde R. (1999) Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur. J. Neurosci. 11, 946–958.

    Article  PubMed  CAS  Google Scholar 

  39. Michael G. J. and Priestley J. V. (1999) Differential expression of the mRNA for the vanilloid receptor subtype 1 in cells of the adult rat dorsal root and nodose ganglia and its downregulation by axotomy. J. Neurosci. 19, 1844–1854.

    PubMed  CAS  Google Scholar 

  40. Sanchez J. F., Krause J. E. and Cortright D. N. (2001) The distribution and regulation of vanilloid receptor VR1 and VR1 5′ splice variant RNA expression in rat. Neuroscience 107, 373–381.

    Article  PubMed  CAS  Google Scholar 

  41. Hudson L. J., Bevan S., Wotherspoon G., Gentry C., Fox A. and Winter J. (2001) VR1 protein expression increases in undamaged DRG neurons after partial nerve injury. Eur. J. Neurosci. 13, 2105–2114.

    Article  PubMed  CAS  Google Scholar 

  42. Fukuoka T., Tokunaga A., Tachibana T., Dai Y., Yamanaka H. and Noguchi K. (2002) VR1, but not P2X3 increases in the spared L4 DRG in rats with L5 spinal nerve ligation. Pain. In press.

  43. Caterina M. J., Schumacher M. A., Tominaga M., Rosen T. A., Levine J. D. and Julius D. (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824.

    Article  PubMed  CAS  Google Scholar 

  44. Tominaga M., Caterina M. J., Malmberg A. B., Rosen T. A., Gilbert H., Skinner K., et al. (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21, 531–543.

    Article  PubMed  CAS  Google Scholar 

  45. Zygmunt P. M., Petersson J., Andersson D. A., Chuang H., Sorgard M., Di M. V., Julius D. and Hogestatt E. D. (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452–457.

    Article  PubMed  CAS  Google Scholar 

  46. Hwang S. W., Cho H., Kwak J., Lee S. Y., Kang C. J., Jung J., et al. (2000) Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc. Natl. Acad. Sci. USA 97, 6155–6160.

    Article  PubMed  CAS  Google Scholar 

  47. Smart D., Gunthorpe M. J., Jerman J. C., Nasir S., Gray J., Muir A. I., et al. (2000) The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br. J. Pharmacol. 129, 227–230.

    Article  PubMed  CAS  Google Scholar 

  48. 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, 429–436.

    Article  PubMed  CAS  Google Scholar 

  49. 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, 428–431.

    Article  PubMed  CAS  Google Scholar 

  50. Bradbury E. J., Burnstock G. and McMahon S. B. (1998) The expression of P2X3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Mol. Cell Neurosci. 4, 256–268.

    Article  Google Scholar 

  51. Vulchanova L., Riedl M. S., Shuster S. J., Stone L. S., Hargreaves K. M., Buell G., et al. (1998) P2X3 is expressed by DRG neurons that terminate in inner lamina II. Eur. J. Neurosci. 10, 3470–3478.

    Article  PubMed  CAS  Google Scholar 

  52. Xu G. Y. and Huang L. Y. (2002) Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons. J. Neurosci. 22, 93–102.

    PubMed  CAS  Google Scholar 

  53. Novakovic S. D., Kassotakis L. C., Oglesby I. B., Smith J. A., Eglen R. M., Ford A. P. and Hunter J. C. (1999) Immunocytochemical localization of P2X3 purinoceptors in sensory neurons in naive rats and following neuropathic injury. Pain 80, 273–282.

    Article  PubMed  CAS  Google Scholar 

  54. Tsuzuki K., Kondo E., Fukuoka T., Dai Y., Tsujino H., Sakagami M. and Noguchi K. (2001) Differential regulation of P2X3 mRNA expression by peripheral nerve injury in intact and injured neurons in the rat sensory ganglia. Pain 91, 351–360.

    Article  PubMed  CAS  Google Scholar 

  55. Chizh B. A. and Illes P. (2001) P2X receptors and nociception. Pharmacol. Rev. 53, 553–568.

    PubMed  CAS  Google Scholar 

  56. Liu T. and Tracey D. J. (2000) ATP P2X receptors play little role in the maintenance of neuropathic hyperalgesia. Neuroreport 11, 1669–1672.

    Article  PubMed  CAS  Google Scholar 

  57. Stanfa L. C., Kontinen V. K. and Dickenson A. H. (2000) Effects of spinally administered P2X receptor agonists and antagonists on the responses of dorsal horn neurones recorded in normal, carrageenan-inflamed and neuropathic rats. Br. J. Pharmacol. 129, 351–359.

    Article  PubMed  CAS  Google Scholar 

  58. Park S. K., Chung K. and Chung J. M. (2000) Effects of purinergic and adrenergic antagonists in a rat model of painful peripheral neuropathy. Pain 87, 171–179.

    Article  PubMed  CAS  Google Scholar 

  59. Li Y., Dorsi M. J., Meyer R. A. and Belzberg A. J. (2000) Mechanical hyperalgesia after an L5 spinal nerve lesion in the rat is not dependent on input from injured nerve fibers. Pain 85, 493–502.

    Article  PubMed  CAS  Google Scholar 

  60. Snider W. D. and McMahon S. B. (1998) Tackling pain at the source: new ideas about nociceptors. Neuron 20, 629–632.

    Article  PubMed  CAS  Google Scholar 

  61. Apfel S. C., Wright D. E., Wiideman A. M., Dormia C., Snider W. D. and Kessler J. A. (1996) Nerve growth factor regulates the expression of brain-derived neurotrophic factor mRNA in the peripheral nervous system. Mol. Cell Neurosci. 7, 134–142.

    Article  PubMed  CAS  Google Scholar 

  62. Winston J., Toma H., Shenoy M. and Pasricha P. J. (2001) Nerve growth factor regulates VR-1 mRNA levels in cultures of adult dorsal root ganglion neurons. Pain 89,

  63. Ogun-Muyiwa P., Helliwell R., McIntyre P. and Winter J. (1999) Glial cell line derived neurotrophic factor (GDNF) regulates VR1 and substance P in cultured sensory neurons. Neuroreport 10, 2107–2111.

    Article  PubMed  CAS  Google Scholar 

  64. Sheen K. and Chung J. M. (1993) Signs of neuropathic pain depend on signals from injured nerve fibers in a rat model. Brain Res. 610, 62–68.

    Article  PubMed  CAS  Google Scholar 

  65. Yoon Y. W., Na H. S. and Chung J. M. (1996) Contributions of injured and intact afferents to neuropathic pain in an experimental rat model. Pain 64, 27–36.

    Article  PubMed  CAS  Google Scholar 

  66. Chung K., Lee B. H., Yoon Y. W. and Chung J. M. (1996) Sympathetic sprouting in the dorsal root ganglia of the injured peripheral nerve in a rat neuropathic pain model. J. Comp. Neurol. 376, 241–252.

    Article  PubMed  CAS  Google Scholar 

  67. Eschenfelder S., Habler H. J. and Janig W. (2000) Dorsal root section elicits signs of neuropathic pain rather than reversing them in rats with L5 spinal nerve injury. Pain 87, 213–219.

    Article  PubMed  CAS  Google Scholar 

  68. Wu G., Ringkamp M., Hartke T. V., Murinson B. B., Campbell J. N., Griffin J. W. and Meyer R. A. (2001) Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers. J. Neurosci. 21, RC140.

    Google Scholar 

  69. Ali Z., Ringkamp M., Hartke T. V., Chien H. F., Flavahan N. A., Campbell J. N. and Meyer R. A. (1999) Uninjured C-fiber nociceptors develop spontaneous activity and alpha-adrenergic senstivity following L6 spinal nerve ligation in monkey. J. Neurophysiol. 81, 455–466.

    PubMed  CAS  Google Scholar 

  70. Michaelis M., Liu X. and Janig W. (2000) Axotomized and intact muscle afferents but no skin afferents develop ongoing discharges of dorsal root ganglion origin after peripheral nerve lesion. J. Neurosci. 20, 2742–2748.

    PubMed  CAS  Google Scholar 

  71. Noguchi K., Kawai Y., Fukuoka T., Senba E. and Miki K. (1995) Substance P induced by peripheral nerve injury in primary afferent sensory neurons and its effect on dorsal column nucleus neurons. J. Neurosci. 15, 7633–7643.

    PubMed  CAS  Google Scholar 

  72. Kashiba H. and Senba E. (1999) Up- and downregulation of BDNF mRNA in distinct subgroups of rat sensory neurons after axotomy. Neuroreport 10, 3561–3565.

    Article  PubMed  CAS  Google Scholar 

  73. Woolf C. J., Shortland P. and Coggeshall R. E. (1992) Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature 355, 75–78.

    Article  PubMed  CAS  Google Scholar 

  74. Miki K., Fukuoka T., Tokunaga A. and Noguchi K. (1998) Calcitonin gene-related peptide increase in the rat spinal dorsal horn and dorsal column nucleus following peripheral nerve injury: up-regulation in a subpopulation of primary afferent sensory neurons. Neuroscience 82, 1243–1252.

    Article  PubMed  CAS  Google Scholar 

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Fukuoka, T., Noguchi, K. Contribution of the spared primary afferent neurons to the pathomechanisms of neuropathic pain. Mol Neurobiol 26, 57–67 (2002). https://doi.org/10.1385/MN:26:1:057

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