Advertisement

Experimental Brain Research

, Volume 196, Issue 1, pp 115–128 | Cite as

Ectopic discharge in Aβ afferents as a source of neuropathic pain

  • Marshall Devor
Review

Abstract

Ectopic discharge in axotomized dorsal root ganglion neurons is a key driver of neuropathic pain. However, the bulk of this activity is generated and carried centrally in large diameter myelinated Aβ afferents, a cell type that normally signals touch and vibration sense. Evidence is considered suggesting that following axotomy, Aβ afferents undergo a change in their electrical characteristics and also in the neurotransmitter complement that they express. This dual phenotypic switching renders them capable of (1) directly driving postsynaptic pain signaling pathways in the spinal cord, and (2) triggering and maintaining central sensitization.

Keywords

Aβ pain Neuropathic pain Phenotypic switch Tactile allodynia 

Notes

Acknowledgment

I am grateful to Michael Tal and Adi Nitzan-Luques for helpful comments on the manuscript, to Yifat Kovalsky for providing Fig. 3 and to Geoff Bove for permitting use of Fig. 5.

References

  1. Abdulla FA, Smith PA (2001) Changes in Na+ channel currents of rat dorsal root ganglion neurons following axotomy and axotomy-induced autotomy. J Neurophysiol 88:2518–2529CrossRefGoogle Scholar
  2. Alano CC, Kauppinen TM, Valls AV, Swanson RA (2006) Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci USA 103:9685–9690PubMedCrossRefGoogle Scholar
  3. Allen BJ, Li J, Menning PM, Rogers SD, Ghilardi J, Mantyh PW, Simone DA (1999) Primary afferent fibers that contribute to increased substance P receptor internalization in the spinal cord after injury. J Neurophysiol 81:1379–1390PubMedGoogle Scholar
  4. Amir R, Michaelis M, Devor M (1999) Membrane potential oscillations in dorsal root ganglion neurons: role in normal electrogenesis and in neuropathic pain. J Neurosci 19:8589–8596PubMedGoogle Scholar
  5. Amir R, Liu CN, Kocsis JD, Devor M (2002) Oscillatory mechanism in primary sensory neurones. Brain 125:421–435PubMedCrossRefGoogle Scholar
  6. Amir R, Kocsis JD, Devor M (2005) Multiple interacting sites of ectopic spike electrogenesis in primary sensory neurons. J Neurosci 25:2576–2585PubMedCrossRefGoogle Scholar
  7. Amir R, Argoff CE, Bennett GJ, Cummins TR, Durieux ME, Gerner P, Gold MS, Porreca F, Strichartz GR (2006) The role of sodium channels in chronic inflammatory and neuropathic pain. J Pain 7:S1–S29PubMedCrossRefGoogle Scholar
  8. Andrew D, Greenspan JD (1999) Mechanical and heat sensitization of cutaneous nociceptors after peripheral inflammation in the rat. J Neurophysiol 82:2649–2656PubMedGoogle Scholar
  9. Apkarian AV, Sosa Y, Sonty S, Levy RM, Harden RN, Parrish TB, Gitelman DR (2004) Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci 24:10410–10415PubMedCrossRefGoogle Scholar
  10. Banik RK, Brennan TJ (2004) Spontaneous discharge and increased heat sensitivity of rat C-fiber nociceptors are present in vitro after plantar incision. Pain 112:204–213PubMedCrossRefGoogle Scholar
  11. Banik RK, Brennan TJ (2008) Sensitization of primary afferents to mechanical and heat stimuli after incision in a novel in vitro mouse glabrous skin-nerve preparation. Pain 138(2):380–391PubMedCrossRefGoogle Scholar
  12. Bao L, Wang HF, Cai HJ, Tong YG, Jin SX, Lu YJ, Grant G, Hokfelt T, Zhang X (2002) Peripheral axotomy induces only very limited sprouting of coarse myelinated afferents into inner lamina II of rat spinal cord. Eur J Neurosci 16:175–185PubMedCrossRefGoogle Scholar
  13. Baron R, Saguer M (1993) Postherpetic neuralgia. Are C-nociceptors involved in signalling and maintenance of tactile allodynia? Brain 116(Pt 6):1477–1496PubMedCrossRefGoogle Scholar
  14. Battaglia AA, Sehayek K, Grist J, McMahon SB, Gavazzi I (2003) EphB receptors and ephrin-B ligands regulate spinal sensory connectivity and modulate pain processing. Nat Neurosci 6:339–340PubMedCrossRefGoogle Scholar
  15. Ben-Chaim Y, Chanda B, Dascal N, Bezanilla F, Parnas I, Parnas H (2006) Movement of ‘gating charge’ is coupled to ligand binding in a G-protein-coupled receptor. Nature 444:106–109PubMedCrossRefGoogle Scholar
  16. Birbaumer N, Lutzenberger W, Montoya P, Larbig W, Unertl K, Topfner S, Grodd W, Taub E, Flor H (1997) Effects of regional anesthesia on phantom limb pain are mirrored in changes in cortical reorganization. J Neurosci 17:5503–5508PubMedGoogle Scholar
  17. Blenk K, Habler H, Janig W (1997) Neomycin and gadolinium applied to an L5 spinal nerve lesion prevent mechanical allodynia-like behaviour in rats. Pain 70:155–165PubMedCrossRefGoogle Scholar
  18. Boada MD, Woodbury CJ (2008) Myelinated skin sensory neurons project extensively throughout adult mouse substantia gelatinosa. J Neurosci 28:2006–2014PubMedCrossRefGoogle Scholar
  19. Boucher TJ, McMahon SB (2001) Neurotrophic factors and neuropathic pain. Curr Opin Pharmacol 1:66–72PubMedCrossRefGoogle Scholar
  20. Campbell AW (1905) Histological studies on the localization of cerebral function. Cambridge University Press, CambridgeGoogle Scholar
  21. Campbell JN, Raja SN, Meyer RA, MacKinnon SE (1988) Myelinated afferents signal the hyperalgesia associated with nerve injury. Pain 32:89–94PubMedCrossRefGoogle Scholar
  22. Cao X, Xie H, Yang R, Lei G, Li F, Li A, Liu C, Liu L (2007) Effects of capsaicin on VGSCs in TRPV1-/- mice. Brain Res 1163:33–43PubMedCrossRefGoogle Scholar
  23. Castro-Lopes JM, Tavares I, Coimbra A (1993) GABA decreases in the spinal cord dorsal horn after peripheral neurectomy. Brain Res 620:287–291PubMedCrossRefGoogle Scholar
  24. Chen Y, Devor M (1998) Ectopic mechanosensitivity in injured sensory axons arises from the site of spontaneous electrogenesis. Eur J Pain 2:165–178PubMedCrossRefGoogle Scholar
  25. Costigan M, Befort K, Karchewski L, Griffin RS, D’Urso D, Allchorne A, Sitarski J, Mannion JW, Pratt RE, Woolf CJ (2002) Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury. BMC Neurosci 3:16–28PubMedCrossRefGoogle Scholar
  26. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG (2006) An SCN9A channelopathy causes congenital inability to experience pain. Nature 444:894–898PubMedCrossRefGoogle Scholar
  27. Craig AD (2003) Pain mechanisms: labeled lines versus convergence in central processing. Annu Rev Neurosci 26:1–30PubMedCrossRefGoogle Scholar
  28. Cummins TR, Dib-Hajj SD, Waxman SG (2004) Electrophysiological properties of mutant Nav 1.7 sodium channels in a painful inherited neuropathy. J Neurosci 24:8232–8236PubMedCrossRefGoogle Scholar
  29. Dalal A, Tata M, Allegre G, Gekiere F, Bons N, Albe-Fessard D (1999) Spontaneous activity of rat dorsal horn cells in spinal segments of sciatic projection following transection of sciatic nerve or of corresponding dorsal roots. Neuroscience 94:217–228PubMedCrossRefGoogle Scholar
  30. Decosterd I, Allchorne A, Woolf CJ (2002) Progressive tactile hypersensitivity after a peripheral nerve crush: non-noxious mechanical stimulus-induced neuropathic pain. Pain 100:155–162PubMedCrossRefGoogle Scholar
  31. Devor M (1999) Unexplained peculiarities of the dorsal root ganglion. Pain suppl 6:S27–S35PubMedCrossRefGoogle Scholar
  32. Devor M (2006a) Centralization, central sensitization and neuropathic pain. Focus on “sciatic chronic constriction injury produces cell-type-specific changes in the electrophysiological properties of rat substantia gelatinosa neurons”. J Neurophysiol 96:522–523PubMedCrossRefGoogle Scholar
  33. Devor M (2006b) Pain cortex, and consciousness. Behav Brain Sci 30:89–90Google Scholar
  34. Devor M (2006c) Peripheral nerve generators of neuropathic pain. In: Campbell JN, Basbaum AI, Dray A, Dubner R, Dworkin RH, Sang CN (eds) Emerging strategies for the treatment of neuropathic pain. IASP Press, Seattle, pp 37–68Google Scholar
  35. Devor M (2006d) Response of nerves to injury in relation to neuropathic pain. In: McMahon SL, Koltzenburg M (eds) Wall and Melzack’s textbook of pain, 5th edn. Churchill Livingstone, London, pp 905–927Google Scholar
  36. Devor M (2007) Central changes after nerve injury. In: Willis W, Schmidt R (eds) Encyclopedia of pain. Springer, BerlinGoogle Scholar
  37. Devor M, Govrin-Lippmann R, Raber P (1985) Corticosteroids suppress ectopic neuronal discharge originating in experimental neuromas. Pain 22:127–137PubMedCrossRefGoogle Scholar
  38. Devor M, Keller CH, Deerinck TJ, Levinson SR, Ellisman M (1989) Na+ channel accumulation on axolemma of afferent endings in nerve-end neuromas in Apteronotus. Neurosci Lett 102:149–154PubMedCrossRefGoogle Scholar
  39. Devor M, Govrin-Lippmann R, Angelides K (1993) Na+ channel immuno-localization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J Neurosci 13:1976–1992PubMedGoogle Scholar
  40. Djouhri L, Lawson SN (2004) Abeta-fiber nociceptive primary afferent neurons: a review of incidence and properties in relation to other afferent A-fiber neurons in mammals. Brain Res Brain Res Rev 46:131–145PubMedCrossRefGoogle Scholar
  41. Duggan AW, Hope PJ, Jarrott B, Schaible HG, Fleetwood-Walker SM (1990) Release, spread and persistence of immunoreactive neurokinin A in the dorsal horn of the cat following cutaneous stimulation. Studies with antibody microprobes. Neuroscience 35:195–202PubMedCrossRefGoogle Scholar
  42. England JD, Happel LT, Kline DG, Gamboni F, Thouron CL, Liu ZP, Levinson SR (1996) Sodium channel accumulation in humans with painful neuromas. Neurology 47:272–276PubMedGoogle Scholar
  43. Fertleman CR, Baker MD, Parker KA, Moffatt S, Elmslie FV, Abrahamsen B, Ostman J, Klugbauer N, Wood JN, Gardiner RM, Rees M (2006) SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron 52:767–774PubMedCrossRefGoogle Scholar
  44. Fields RD (1996) Signaling from neural impulses to genes. Neuroscientist 2:315–325Google Scholar
  45. Fields RD, Eshete F, Dudek S, Ozsarac N, Stevens B (2001) Regulation of gene expression by action potentials: dependence on complexity in cellular information processing. Novartis Found Symp 239:160–172PubMedCrossRefGoogle Scholar
  46. Flor H, Elbert T, Knecht S, Wienbruch C, Pantev C, Birbaumer N, Larbig W, Taub E (1995) Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature 375:482–484PubMedCrossRefGoogle Scholar
  47. Fried K, Govrin-Lippmann R, Rosenthal F, Ellisman M, Devor M (1991) Ultra-structure of afferent axon endings in a neuroma. J Neurocytol 20:682–701PubMedCrossRefGoogle Scholar
  48. Gold MS, Reichling DB, Shuster MJ, Levine JD (1996) Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors. Proc Natl Acad Sci USA 93:1108–1112PubMedCrossRefGoogle Scholar
  49. Gonzalez JC, Egea J, Del Carmen Godino M, Fernandez-Gomez FJ, Sanchez-Prieto J, Gandia L, Garcia AG, Jordan J, Hernandez-Guijo JM (2007) Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca(2+) signalling in hippocampal neurons. Eur J Neurosci 26:2481–2495PubMedCrossRefGoogle Scholar
  50. Gracely R, Lynch S, Bennett G (1992) Painful neuropathy: altered central processing, maintained dynamically by peripheral input. Pain 51:175–194PubMedCrossRefGoogle Scholar
  51. Gu X, Wang S, Yang L, Sung B, Lim G, Mao J, Zeng Q, Chang Y (2007) Time-dependent effect of epidural steroid on pain behavior induced by chronic compression of dorsal root ganglion in rats. Brain Res 1174:39–46PubMedCrossRefGoogle Scholar
  52. Haeseler G, Tetzlaff D, Bufler J, Dengler R, Munte S, Hecker H, Leuwer M (2003) Blockade of voltage-operated neuronal and skeletal muscle sodium channels by S(+)- and R(−)-ketamine. Anesth Analg 96:1019–1026PubMedCrossRefGoogle Scholar
  53. Han H, Lee D, Chung J (2000) Characteristics of ectopic discharges in a rat neuropathic pain model. Pain 84:253–261PubMedCrossRefGoogle Scholar
  54. Harris AJ (1999) Cortical origin of pathological pain. Lancet 354:1464–1466PubMedCrossRefGoogle Scholar
  55. Harty TP, Dib-Hajj SD, Tyrrell L, Blackman R, Hisama FM, Rose JB, Waxman SG (2006) Nav 1.7 mutant A863P in erythromelalgia: effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons. J Neurosci 26:12566–12575PubMedCrossRefGoogle Scholar
  56. Hoffmann T, Sauer SK, Horch RE, Reeh PW (2008) Sensory transduction in peripheral nerve axons elicits ectopic action potentials. J Neurosci 28(RC140):6281–6284PubMedCrossRefGoogle Scholar
  57. Hughes DI, Scott DT, Riddell JS, Todd AJ (2007) Upregulation of substance P in low-threshold myelinated afferents is not required for tactile allodynia in the chronic constriction injury and spinal nerve ligation models. J Neurosci 27:2035–2044PubMedCrossRefGoogle Scholar
  58. Ibuki T, Hama AT, Wang XT, Pappas GD, Sagen J (1997) Loss of GABA-immunoreactivity in the spinal dorsal horn of rats with peripheral nerve injury and promotion of recovery by adrenal medullary grafts. Neuroscience 76:845–858PubMedCrossRefGoogle Scholar
  59. Kaczmarek LK (2006) Non-conducting functions of voltage-gated ion channels. Nat Rev Neurosci 7:761–771PubMedCrossRefGoogle Scholar
  60. Kalso E (1997) Prevention of chronicity. In: Jensen TS, Turner JA, Wiesenfeld-Hallin ZH (eds) Proceedings of the 8th world congress on pain. Progress in pain research and management, vol 8. IASP Press, Seattle, pp 215–230Google Scholar
  61. Kapoor R, Li Y-G, Smith K (1997) Slow sodium-dependent potential oscillations contribute to ectopic firing in mammalian demyelinated axons. Brain 120:647–652PubMedCrossRefGoogle Scholar
  62. Khan GM, Chen SR, Pan HL (2002) Role of primary afferent nerves in allodynia caused by diabetic neuropathy in rats. Neuroscience 114:291–299PubMedCrossRefGoogle Scholar
  63. Kim SH, Chung JM (1992) An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50:355–363PubMedCrossRefGoogle Scholar
  64. Kim HK, Schattschneider J, Lee I, Chung K, Baron R, Chung JM (2007) Prolonged maintenance of capsaicin-induced hyperalgesia by brief daily vibration stimuli. Pain 129:93–101PubMedCrossRefGoogle Scholar
  65. Kinnman E, Levine J (1995) Sensory and sympathetic contributions to nerve injury-induced sensory abnormalities in the rat. Neuroscience 64:751–767PubMedCrossRefGoogle Scholar
  66. Klein JP, Tendi EA, Dib-Hajj SD, Fields RD, Waxman SG (2003) Patterned electrical activity modulates sodium channel expression in sensory neurons. J Neurosci Res 74:192–198PubMedCrossRefGoogle Scholar
  67. Kocsis JD, Devor M (2000) Altered excitability of large diameter cutaneous afferents following nerve injury: consequences for chronic pain. In: Devor M, Rowbotham MC, Wiesenfeld-Hallin Z (eds), Proceedings of the 9th world congress on pain, progress in pain research and management, vol 16, IASP Press, SeattleGoogle Scholar
  68. Koltzenburg M, Kees S, Budweiser S, Ochs G, Toyka KV (1994a) The properties of unmyelinated nociceptive afferents change in a painful chronic constriction neuropathy. In: Gebhart G, Hammond D, Jensen T (eds) Progress in pain research and management, vol 2. IASP Press, Seattle, pp 511–521Google Scholar
  69. Koltzenburg M, Torebjork H, Wahren L (1994b) Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain 117:579–591PubMedCrossRefGoogle Scholar
  70. Kovalsky Y, Amir R, Devor M (2008) Subthreshold oscillations facilitate neuropathic spike discharge by overcoming membrane accommodation. Exp Neurol 210:194–206PubMedCrossRefGoogle Scholar
  71. Lawson SN (2002) Phenotype and function of somatic primary afferent nociceptive neurones with C-Adelta- or Aalpha/beta-fibres. Exp Physiol 87:239–244PubMedCrossRefGoogle Scholar
  72. Lever IJ, Bradbury EJ, Cunningham JR, Adelson DW, Jones MG, McMahon SB, Marvizon JC, Malcangio M (2001) Brain-derived neurotrophic factor is released in the dorsal horn by distinctive patterns of afferent fiber stimulation. J Neurosci 21:4469–4477PubMedGoogle Scholar
  73. Li M, West JW, Lai Y, Scheuer Y, Catterall WA (1992) Functional modulation of brain sodium channels by cAMP-dependent phosphorylation. Neuron 8:1151–1159PubMedCrossRefGoogle Scholar
  74. Li Y, Dorsi MJ, Meyer RA, Belzberg AJ (2000) Mechanical hyperalgesia after an L5 spinal nerve lesion in the rat is not dependent on input from injured nerve fibers. Pain 85:493–502PubMedCrossRefGoogle Scholar
  75. Lindblom U, Verrillo RT (1979) Sensory functions in chronic neuralgia. J Neurol Neurosurg Psychiatry 42:422–435PubMedCrossRefGoogle Scholar
  76. Liu C-N, Michaelis M, Amir R, Devor M (2000a) Spinal nerve injury enhances subthreshold membrane potential oscillations in DRG neurons: relation to neuropathic pain. J Neurophysiol 84:205–215PubMedGoogle Scholar
  77. Liu C-N, Wall PD, Ben-Dor E, Michaelis M, Amir R, Devor M (2000b) Tactile allodynia in the absence of C-fiber activation: altered firing properties of DRG neurons following spinal nerve injury. Pain 85:503–521PubMedCrossRefGoogle Scholar
  78. Liu X, Eschenfelder S, Blenk K-H, Janig W, Habler H-J (2000c) Spontaneous activity of axotomized afferent neurons after L5 spinal nerve injury in rats. Pain 84:309–318PubMedCrossRefGoogle Scholar
  79. Liu L, Oortgiesen M, Li L, Simon SA (2001a) Capsaicin inhibits activation of voltage-gated sodium currents in capsaicin-sensitive trigeminal ganglion neurons. J Neurophysiol 85:745–758PubMedGoogle Scholar
  80. Liu CN, Raber P, Ziv-Sefer S, Devor M (2001b) Hyperexcitability in sensory neurons of rats selected for high versus low neuropathic pain phenotype. Neuroscience 105:265–275PubMedCrossRefGoogle Scholar
  81. Ma W, Ramer MS, Bisby MA (1999) Increased calcitonin gene-related peptide immunoreactivity in gracile nucleus after partial sciatic nerve injury: age-dependent and originating from spared sensory neurons. Exp Neurol 159:459–473PubMedCrossRefGoogle Scholar
  82. Malcangio M, Ramer MS, Jones MG, McMahon SB (2000) Abnormal substance P release from the spinal cord following injury to primary sensory neurons. Eur J Neurosci 12:397–399PubMedCrossRefGoogle Scholar
  83. Marchand JE, Wurm WH, Kato T, Kream RM (1994) Altered tachykinin expression by dorsal root ganglion neurons in a rat model of neuropathic pain. Pain 58:219–231PubMedCrossRefGoogle Scholar
  84. Matsumoto M, Inoue M, Hald A, Xie W, Ueda H (2006) Inhibition of paclitaxel-induced A-fiber hypersensitization by gabapentin. J Pharmacol Exp Ther 318:735–740PubMedCrossRefGoogle Scholar
  85. Matzner O, Devor M (1994) Hyperexcitability at sites of nerve injury depends on voltage -sensitive Na+ channels. J Neurophysiol 72:349–357PubMedGoogle Scholar
  86. Meiri H, Spira ME, Parnas I (1981) Membrane conductance and action potential of a regenerating axonal tip. Science 211:709–712PubMedCrossRefGoogle Scholar
  87. Melzack R (1989) Phantom limbs the self and the brain. Can Psychol 30:1–16CrossRefGoogle Scholar
  88. Michael GJ, Averill S, Shortland PJ, Yan Q, Priestley JV (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 11:3539–3551PubMedCrossRefGoogle Scholar
  89. Michaelis M, Blenk K-H, Janig W, Vogel C (1995) Development of spontaneous activity and mechano-sensitivity in axotomized afferent nerve fibers during the first hours after nerve transection in rats. J Neurophysiol 74:1020–1027PubMedGoogle Scholar
  90. Miki K, Fukuoka T, Tokunaga A, 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 82:1243–1252PubMedCrossRefGoogle Scholar
  91. Molander C, Hongpaisan J, Persson JK (1994) Distribution of c-fos expressing dorsal horn neurons after electrical stimulation of low threshold sensory fibers in the chronically injured sciatic nerve. Brain Res 644:74–82PubMedCrossRefGoogle Scholar
  92. Nagy JI, Buss M, Mallory B (1986) Autotomy in rats after peripheral nerve section: lack of effect of topical nerve or neonatal capsaicin treatment. Pain 24:75–86PubMedCrossRefGoogle Scholar
  93. Nassar MA, Baker MD, Levato A, Ingram R, Mallucci G, McMahon SB, Wood JN (2006) Nerve injury induces robust allodynia and ectopic discharges in Nav1.3 null mutant mice. Mol Pain 2:33PubMedCrossRefGoogle Scholar
  94. Neumann S, Doubell TP, Leslie TA, Woolf CJ (1996) Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons. Nature 384:360–364PubMedCrossRefGoogle Scholar
  95. Neumann S, Braz JM, Skinner K, Llewellyn-Smith IJ, Basbaum AI (2008) Innocuous not noxious, input activates PKCgamma interneurons of the spinal dorsal horn via myelinated afferent fibers. J Neurosci 28:7936–7944PubMedCrossRefGoogle Scholar
  96. Noguchi K, Kawai Y, Fukuoka T, Senba E, 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 15:7633–7643PubMedGoogle Scholar
  97. Nordin M, Nystrom B, Wallin U, Hagbarth K-E (1984) Ectopic sensory discharges and paresthesiae in patients with disorders of peripheral nerves dorsal roots and dorsal columns. Pain 20:231–245PubMedCrossRefGoogle Scholar
  98. Obata K, Yamanaka H, Dai Y, Mizushima T, Fukuoka T, Tokunaga A, Noguchi K (2004) Differential activation of MAPK in injured and uninjured DRG neurons following chronic constriction injury of the sciatic nerve in rats. Eur J Neurosci 20:2881–2895PubMedCrossRefGoogle Scholar
  99. Ossipov M, Bian D, Malan TJ, Lai J, Porreca F (1999) Lack of involvement of capsaicin-sensitive primary afferents in nerve-ligation injury induced tactile allodynia in rats. Pain 79:127–133PubMedCrossRefGoogle Scholar
  100. Pan HL, Eisenach JC, Chen SR (1999) Gabapentin suppresses ectopic nerve discharges and reverses allodynia in neuropathic rats. J Pharmacol Exp Ther 288:1026–1030PubMedGoogle Scholar
  101. Persson A-K, Gebauer M, Jordan S, Metz-Weidmann C, Schulte AM, Schneider H-C, Ding-Pfennigdorff D, Thun J, Xu X-J, Wiesenfeld-Hallin Z, Darvasi A, Fried K, Devor M (2009) Correlational analysis for identifying genes whose regulation contributes to chronic neuropathic pain. Mol Pain (in press)Google Scholar
  102. Pfeffer SR (2007) Unsolved mysteries in membrane traffic. Annu Rev Biochem 76:629–645PubMedCrossRefGoogle Scholar
  103. Pitcher GM, Henry JL (2004) Nociceptive response to innocuous mechanical stimulation is mediated via myelinated afferents and NK-1 receptor activation in a rat model of neuropathic pain. Exp Neurol 186:173–197PubMedCrossRefGoogle Scholar
  104. Pitcher GM, Henry JL (2008) Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy. Exp Neurol 214:219–228PubMedCrossRefGoogle Scholar
  105. Puil E, Gimbarzevsky B, Spigelman I (1988) Primary involvement of K+ conductance in membrane resonance of trigeminal root ganglion neurons. J Neurophysiol 59:77–89PubMedGoogle Scholar
  106. Reeh PW, Bayer J, Kocher L, Handwerker HO (1987) Sensitization of nociceptive cutaneous nerve fibers from the rat’s tail by noxious mechanical stimulation. Exp Brain Res 65:505–512PubMedCrossRefGoogle Scholar
  107. Rizzo M, Kocsis J, Waxman S (1996) Mechanism of paraesthesiae and hyperaesthesiae: role of Na+ channel heterogeneity. Eur Neurol 36:3–12PubMedCrossRefGoogle Scholar
  108. Saade NE, Baliki M, El-Khoury C, Hawwa N, Atweh SF, Apkarian AV, Jabbur SJ (2002) The role of the dorsal columns in neuropathic behavior: evidence for plasticity and non-specificity. Neuroscience 115:403–413PubMedCrossRefGoogle Scholar
  109. Schaible HG, Hope PJ, Lang CW, Duggan AW (1992) Calcitonin gene-related peptide causes intraspinal spreading of substance P released by peripheral stimulation. Eur J Neurosci 4:750–757PubMedCrossRefGoogle Scholar
  110. Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjork E, Handwerker H (1995) Novel classes of responsive and unresponsive C nociceptors in human skin. J Neurosci 15:333–341PubMedGoogle Scholar
  111. Schoffnegger D, Ruscheweyh R, Sandkuhler J (2008) Spread of excitation across modality borders in spinal dorsal horn of neuropathic rats. Pain 135:300–310PubMedCrossRefGoogle Scholar
  112. Sheen K, Chung JM (1993) Signs of neuropathic pain depend on signals from injured nerve fibers in a rat model. Brain Res 610:62–68PubMedCrossRefGoogle Scholar
  113. Shehab SA, Spike RC, Todd AJ (2004) Do central terminals of intact myelinated primary afferents sprout into the superficial dorsal horn of rat spinal cord after injury to a neighboring peripheral nerve? J Comp Neurol 474:427–437PubMedCrossRefGoogle Scholar
  114. Sherrington CS (1906) The integrative action of the nervous system. Constable, LondonGoogle Scholar
  115. Shim B, Kim DW, Kim BH, Nam TS, Leem JW, Chung JM (2005) Mechanical and heat sensitization of cutaneous nociceptors in rats with experimental peripheral neuropathy. Neuroscience 132:193–201PubMedCrossRefGoogle Scholar
  116. Shir Y, Seltzer Z (1990) A-fibers mediate mechanical hyperesthesia and allodynia and C-fibers mediate thermal hyperalgesia in a new model of causalgiform pain disorders in rats. Neurosci Lett 115:62–67PubMedCrossRefGoogle Scholar
  117. Sotgiu ML, Biella G, Riva L (1994) A study of early ongoing activity in dorsal horn units following sciatic nerve constriction. NeuroReport 5:2609–2612PubMedGoogle Scholar
  118. Sukhotinsky I, Ben-Dor E, Raber P, Devor M (2004) Key role of the dorsal root ganglion in neuropathic tactile hypersensibility. Eur J Pain 8:135–143PubMedCrossRefGoogle Scholar
  119. Sun H, Ren K, Zhong CM, Ossipov MH, Malan TP, Lai J, Porreca F (2001) Nerve injury-induced tactile allodynia is mediated via ascending spinal dorsal column projections. Pain 90:105–111PubMedCrossRefGoogle Scholar
  120. Sun Q, Tu H, Xing GG, Han JS, Wan Y (2005) Ectopic discharges from injured nerve fibers are highly correlated with tactile allodynia only in early but not late, stage in rats with spinal nerve ligation. Exp Neurol 191:128–136PubMedCrossRefGoogle Scholar
  121. Tal M, Kim J, Back SK, Na HS, Devor M (2006) Onset of ectopic firing in the Chung model of neuropathic pain coincides with the onset of tactile allodynia. In: Flor H, Kalso E, Dostrovsky JO (eds), Proceedings of the 11th world congress on pain, IASP Press, Seattle, pp 119–130Google Scholar
  122. Tessler MJ, Kleiman SJ (1994) Spinal anaesthesia for patients with previous lower limb amputations. Anaesthesia 49:439–441PubMedCrossRefGoogle Scholar
  123. Torebjork H, Lundberg L, LaMotte R (1992) Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol 448:765–780PubMedGoogle Scholar
  124. Tracey I, Mantyh PW (2007) The cerebral signature for pain perception and its modulation. Neuron 55:377–391PubMedCrossRefGoogle Scholar
  125. Tsuboi Y, Takeda M, Tanimoto T, Ikeda M, Matsumoto S, Kitagawa J, Teramoto K, Simizu K, Yamazaki Y, Shima A, Ren K, Iwata K (2004) Alteration of the second branch of the trigeminal nerve activity following inferior alveolar nerve transection in rats. Pain 111:323–334PubMedCrossRefGoogle Scholar
  126. Vallbo AB, Hagbarth KE, Torebjork HE, Wallin BG (1979) Somatosensory proprioceptive, and sympathetic activity in human peripheral nerves. Physiol Rev 59:919–957PubMedGoogle Scholar
  127. Wagner LE 2nd, Gingrich KJ, Kulli JC, Yang J (2001) Ketamine blockade of voltage-gated sodium channels: evidence for a shared receptor site with local anesthetics. Anesthesiology 95:1406–1413PubMedCrossRefGoogle Scholar
  128. Wang GK, Russell C, Wang SY (2004) State-dependent block of voltage-gated Na+ channels by amitriptyline via the local anesthetic receptor and its implication for neuropathic pain. Pain 110:166–174PubMedCrossRefGoogle Scholar
  129. Watkins LR, Maier SF (2002) Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 82:981–1011PubMedGoogle Scholar
  130. Waxman SG (ed) (2002) Sodium channels and neuronal hyperexcitability, Novartis Found Symp, vol 241, Wiley, West Sussex, UK, 232 pGoogle Scholar
  131. Waxman SG, Dib-Hajj S (2005) Erythermalgia: molecular basis for an inherited pain syndrome. Trends Mol Med 11:555–562PubMedCrossRefGoogle Scholar
  132. Waxman SG, Kocsis JD, Black JA (1994) Type III sodium channel mRNA is expressed in embryonic but not in adult spinal sensory neurons, and is re-expressed following axotomy. J Neurophysiol 72:466–470PubMedGoogle Scholar
  133. Weissner W, Winterson BJ, Stuart-Tilley A, Devor M, Bove GM (2006) Time course of substance P expression in dorsal root ganglia following complete spinal nerve transection. J Comp Neurol 497:78–87PubMedCrossRefGoogle Scholar
  134. Willis W (1992) Hyperalgesia and allodynia. Raven Press, New York, pp 173–385, 400Google Scholar
  135. Woolf CJ, Salter MW (2000) Neuronal plasticity: increasing the gain in pain. Science 288:1765–1769PubMedCrossRefGoogle Scholar
  136. Woolf C, Thompson S (1991) 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 44:293–299PubMedCrossRefGoogle Scholar
  137. Wu G, Ringkamp M, Hartke TV, Murinson BB, Campbell JN, Griffin JW, Meyer RA (2001a) Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers. J Neurosci 21(8):RC140PubMedGoogle Scholar
  138. Wu N, Hsiao C-F, Chandler S (2001b) Membrane resonance and subthreshold membrane oscillations in mesencephalic V neurons: participants in burst generation. J Neurosci 21:3729–3739PubMedGoogle Scholar
  139. Xiao HS, Huang QH, Zhang FX, Bao L, Lu YJ, Guo C, Yang L, Huang WJ, Fu G, Xu SH, Cheng XP, Yan Q, Zhu ZD, Zhang X, Chen Z, Han ZG, Zhang X (2002) Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc Natl Acad Sci USA 99:8360–8365PubMedCrossRefGoogle Scholar
  140. Xie W, Strong JA, Meij JT, Zhang JM, Yu L (2005) Neuropathic pain: early spontaneous afferent activity is the trigger. Pain 116:243–256PubMedCrossRefGoogle Scholar
  141. Yang RH, Xing JL, Duan JH, Hu SJ (2005) Effects of gabapentin on spontaneous discharges and subthreshold membrane potential oscillation of type A neurons in injured DRG. Pain 116:187–193PubMedCrossRefGoogle Scholar
  142. Zheng JH, Song XJ (2005) Abeta-afferents activate neurokinin-1 receptor in dorsal horn neurons after nerve injury. Neuroreport 16:715–719PubMedCrossRefGoogle Scholar
  143. Zhou ZS, Zhao ZQ (2000) Ketamine blockage of both tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels of rat dorsal root ganglion neurons. Brain Res Bull 52:427–433PubMedCrossRefGoogle Scholar
  144. Ziegler EA, Magerl W, Meyer RA, Treede RD (1999) Secondary hyperalgesia to punctate mechanical stimuli. Central sensitization to A-fibre nociceptor input. Brain 122:2245–2257PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of Cell and Developmental Biology, Institute of Life Sciences and Center for Research on PainHebrew University of JerusalemJerusalemIsrael

Personalised recommendations