Sensory Nerves pp 589-615

Part of the Handbook of Experimental Pharmacology book series (HEP, volume 194)

Future Treatment Strategies for Neuropathic Pa

  • Fabien March
  • Nicholas G. Jones
  • Stephen B. McMahon
Chapter

Abstract

The prevalence of people suffering from chronic pain is extremely high and pain affects millions of people worldwide. As such, persistent pain represents a major health problem and an unmet clinical need. The reason for the high incidence of chronic pain patients is in a large part due to a paucity of effective pain control. An important reason for poor pain control is undoubtedly a deficit in our understanding of the underlying causes of chronic pain and as a consequence our arsenal of analgesic therapies is limited. However, there is considerable hope for the development of new classes of analgesic drugs by targeting novel processes contributing to clinically relevant pain. In this chapter we highlight a number of molecular species which are potential therapeutic targets for future neuropathic pain treatments. In particular, the roles of voltage-gated ion channels, neuroinflammation, protein kinases and neurotrophins are discussed in relation to the generation of neuropathic pain and how by targeting these molecules it may be possible to provide better pain control than is currently available.

Keywords

Neuropathic pain Sodium channels Neuropeptides Cannabinoids 

References

  1. Abbadie C, Lindia JA, Cumiskey AM, Peterson LB, Mudgett JS, Bayne EK, DeMartino JA, MacIntyre DE, Forrest MJ (2003) Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc Natl Acad Sci USA 100:7947–7952PubMedGoogle Scholar
  2. Ahmad S, Dahllund L, Eriksson AB, Hellgren D, Karlsson U, Lund PE, Meijer IA, Meury L, Mills T, Moody A, Morinville A, Morten J, O'Donnell D, Raynoschek C, Salter H, Rouleau GA, Krupp JJ (2007) A stop codon mutation in SCN9A causes lack of pain sensation. Hum Mol Genet 16:2114–2121PubMedGoogle Scholar
  3. Amir R, Argoff CE, Bennett GJ, Cummins TR (2006) The role of sodium channels in chronic inflammatory and neuropathic pain. J Pain 7:S1–S29PubMedGoogle Scholar
  4. Aumeerally N, Allen G, Sawynok J (2004) Glutamate-evoked release of adenosine and regulation of peripheral nociception. Neuroscience 127:1–11PubMedGoogle Scholar
  5. Balkowiec A, Katz DM (2000) Activity-dependent release of endogenous brain-derived neurotrophic factor from primary sensory neurons detected by ELISA in situ. J Neurosci 20:7417–7423PubMedGoogle Scholar
  6. Ballet S, Aubel B, Mauborgne A, Polienor H, Farre A, Cesselin F, Hamon M, Bourgoin AS (2001) The novel analgesic, cizolirtine, inhibits the spinal release of substance P and CGRP in rats. Neuropharmacology 40:578–589PubMedGoogle Scholar
  7. Barakat-Walter I (1996) Brain-derived neurotrophic factor-like immunoreactivity is localized mainly in small sensory neurons of rat dorsal root ganglia. J Neurosci Methods 68:281–288PubMedGoogle Scholar
  8. Bennett DL, Koltzenburg M, Priestley JV, Shelton DL, McMahon SB (1998a) Endogenous nerve growth factor regulates the sensitivity of nociceptors in the adult rat. Eur J Neurosci 10:1282–1291PubMedGoogle Scholar
  9. Bennett G, al-Rashed S, Hoult JRS, Brain SD (1998b) Nerve growth factor induced hyperalgesia in the rat hind paw is dependent on circulating neutrophils. Pain 77:315–322PubMedGoogle Scholar
  10. Bennett DL (2001) Neurotrophic factors; important regulators of nociceptive function. Neuroscientist 7:13–17Google Scholar
  11. Blackburn-Munro G, Jensen BS (2003) The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic pain. Eur J Pharmacol 460:109–116PubMedGoogle Scholar
  12. Blits B, Bunge MB (2006) Direct gene therapy for repair of the spinal cord. J Neurotrauma 23:508–520PubMedGoogle Scholar
  13. Boucher TJ, Okuse K, Bennett DL, Munson JB, Wood JN, McMahon SB (2000) Potent analgesic effects of GDNF in neuropathic pain states. Science 290:124–127PubMedGoogle Scholar
  14. Bulaj G, Zhang MM, Green BR, Fiedler B, Layer RT, Wei S, Nielsen JS, Low SJ, Klein BD, Wagstaff JD, Chicoine L, Harty TP, Terlau H, Yoshikami D, Olivera BM (2006) Synthetic mu O-conotoxin MrVIB blocks TTX-resistant sodium channel Nav1.8 and has a long-lasting analgesic activity. Biochemistry 45:7404–7414PubMedGoogle Scholar
  15. Chien LY, Cheng JK, Chu DC, Cheng CF, Tsaur ML (2007) Reduced expression of A-type potassium channels in primary sensory neurons induces mechanical hypersensitivity. J Neurosci 27:9855–9865PubMedGoogle Scholar
  16. Clark AK, D'Aquisto F, Gentry C, Marchand F, McMahon SB, Malcangio M (2006) Rapid co-release of interleukin 1beta and caspase 1 in spinal cord inflammation. J Neurochem 99:868–880PubMedGoogle Scholar
  17. Clark AK, Yip PK, Grist J, Gentry C, Staniland AA, Marchand F, Dehvari M, Wotherspoon G, Winter J, Ullah J, Bevan S, Malcangio M (2007) Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc Natl Acad Sci USA 104:10655–10660PubMedGoogle Scholar
  18. Clatworthy AL, Illich PA, Castro GA, Walters ET (1995) Role of peri-axonal inflammation in the development of thermal hyperalgesia and guarding behavior in a rat model of neuropathic pain. Neurosci Lett 184:5–8PubMedGoogle Scholar
  19. Cox B (2000) Calcium channel blockers and pain therapy. Curr Rev Pain 4:488–498PubMedGoogle Scholar
  20. 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 444:894–898PubMedGoogle Scholar
  21. Crowley C, Spencer SD, Nishimura MC, Chen KS, Pitts-Meek S, Armanini MP, Ling LH, McMahon SB, Shelton DL, Levinson AD (1994) Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell 76:1001–1011PubMedGoogle Scholar
  22. Cruccu G, Aziz TZ, Garcia-Larrea L, Hansson P, Jensen TS, Lefaucheur JP, Simpson BA, Taylor RS (2007) EFNS guidelines on neurostimulation therapy for neuropathic pain. Eur J Neurol 14:952–970PubMedGoogle Scholar
  23. Cui JG, Holmin S, Mathiesen T, Meyerson BA, Linderoth B (2000) Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy. Pain 88:239–248PubMedGoogle Scholar
  24. Cummins TR, Sheets PL, Waxman SG (2007) The roles of sodium channels in nociception: implications for mechanisms of pain. Pain 131:243–257PubMedGoogle Scholar
  25. Daulhac L, Mallet C, Courteix C, Etienne M, Duroux E, Privat AM, Eschalier A, Fialip J (2006) Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-d-aspartate-dependent mechanisms. Mol Pharmacol 70:1246–1254PubMedGoogle Scholar
  26. Doggrell SA (2004) Intrathecal ziconotide for refractory pain. Expert Opin Investig Drugs 13:875–877PubMedGoogle Scholar
  27. Dost R, Rostock A, Rundfeldt C (2004) The anti-hyperalgesic activity of retigabine is mediated by KCNQ potassium channel activation. Naunyn Schmiedebergs Arch Pharmacol 369: 382–390PubMedGoogle Scholar
  28. Dworkin RH, O'Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy RK, Rice ASC, Stacey BR, Treede RD, Turk DC, Wallace MS (2007) Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132:237–251PubMedGoogle Scholar
  29. Ekberg J, Jayamanne A, Vaughan CW, Aslan S, Thomas L, Mouldt J, Drinkwater R, Baker MD, Abrahamsen B, Wood JN, Adams DJ, Christie MJ, Lewis RJ (2006) mu O-conotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits. Proc Natl Acad Sci USA 103:17030–17035PubMedGoogle Scholar
  30. Flatters SJ, Fox AJ, Dickenson AH (2004) Nerve injury alters the effects of interleukin-6 on nociceptive transmission in peripheral afferents. Eur J Pharmacol 484:183–191PubMedGoogle Scholar
  31. Fukuoka T, Kondo E, Dai Y, Hashimoto N, Noguchi K (2001) Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model. J Neurosci 21:4891–4900PubMedGoogle Scholar
  32. Galli SJ, Nakae S, Tsai M (2005) Mast cells in the development of adaptive immune responses. Nat Immunol 6:135–142PubMedGoogle Scholar
  33. Garcia-Larrea L, Peyron R (2007) Motor cortex stimulation for neuropathic pain: from phenomenology to mechanisms. Neuroimage 37(Suppl 1):S71–S79PubMedGoogle Scholar
  34. Garraway SM, Petruska JC, Mendell LM (2003) BDNF sensitizes the response of lamina II neurons to high threshold primary afferent inputs. Eur J Neurosci 18:2467–2476PubMedGoogle Scholar
  35. George A, Schmidt C, Weishaupt A, Toyka KV, Sommer C (1999) Serial determination of tumor necrosis factor-alpha content in rat sciatic nerve after chronic constriction injury. Exp Neurol 160:124–132PubMedGoogle Scholar
  36. George A, Marziniak M, Schafers M, Toyka KV, Sommer C (2000) Thalidomide treatment in chronic constrictive neuropathy decreases endoneurial tumor necrosis factor-alpha, increases interleukin-10 and has long-term effects on spinal cord dorsal horn met-enkephalin. Pain 88:267–275PubMedGoogle Scholar
  37. George A, Buehl A, Sommer C (2005) Tumor necrosis factor receptor 1 and 2 proteins are differentially regulated during Wallerian degeneration of mouse sciatic nerve. Exp Neurol 192:163–166PubMedGoogle Scholar
  38. Glorioso JC, Fink DJ (2004) Herpes vector-mediated gene transfer in treatment of diseases of the nervous system. Annu Rev Microbiol 58:253–271PubMedGoogle Scholar
  39. Goss JR (2007) The therapeutic potential of gene transfer for the treatment of peripheral neuropathies. Expert Rev Mol Med 9:1–20PubMedGoogle Scholar
  40. Ha SO, Kim JK, Hong HS, Kim DS, Cho HJ (2001) Expression of brain-derived neurotrophic factor in rat dorsal root ganglia, spinal cord and gracile nuclei in experimental models of neuropathic pain. Neuroscience 107:301–309PubMedGoogle Scholar
  41. Hains BC, Klein JP, Saab CY, Craner MJ, Black JA, Waxman SG (2003) Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J Neurosci 23:8881–8892PubMedGoogle Scholar
  42. Hains BC, Saab CY, Klein JP, Craner MJ, Waxman SG (2004) Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury. J Neurosci 24:4832–4839PubMedGoogle Scholar
  43. Hao S, Mata M, Glorioso JC, Fink DJ (2006) HSV-mediated expression of interleukin-4 in dorsal root ganglion neurons reduces neuropathic pain. Mol Pain 2:6PubMedGoogle Scholar
  44. Hao S, Mata M, Glorioso JC, Fink DJ (2007) Gene transfer to interfere with TNFalpha signaling in neuropathic pain. Gene Ther 14:1010–1016PubMedGoogle Scholar
  45. Hashizume H, Rutkowski MD, Weinstein JN, Deleo JA (2000) Central administration of methotrexate reduces mechanical allodynia in an animal model of radiculopathy/sciatica. Pain 87:159–169PubMedGoogle Scholar
  46. Heppenstall PA, Lewin GR (2001) BDNF but not NT-4 is required for normal flexion reflex plasticity and function. Proc Natl Acad Sci USA 98:8107–8112PubMedGoogle Scholar
  47. Heumann R, Lindholm D, Bandtlow C, Meyer M, Radeke MJ, Misko TP, Shooter E, Thoenen H (1987) Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: role of macrophages. Proc Natl Acad Sci USA 84:8735–8739PubMedGoogle Scholar
  48. Jarvis MF, Honore P, Shieh CC, Chapman M, Joshi S, Zhang XF, Kort M, Carroll W, Marron B, Atkinson R, Thomas J, Liu D, Krambis M, Liu Y, McGaraughty S, Chu K, Roeloffs R, Zhong CM, Mikusa JP, Hernandez G, Gauvin D, Wade C, Zhu C, Pai M, Scanio M, Shi L, Drizin I, Gregg R, Matulenko M, Hakeem A, Grosst M, Johnson M, Marsh K, Wagoner PK, Sullivan JP, Faltynek CR, Krafte DS (2007) A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci USA 104:8520–8525PubMedGoogle Scholar
  49. Ji RR, Suter MR (2007) p38 MAPK, microglial signaling, and neuropathic pain. Mol Pain 3:33PubMedGoogle Scholar
  50. Ji RR, Baba H, Brenner GJ, Woolf CJ (1999) Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci 2:1114–1119PubMedGoogle Scholar
  51. Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Zhang YQ (2007) Protein kinases as potential targets for the treatment of pathological pain. Handb Exp Pharmacol 359–389Google Scholar
  52. Jin SX, Zhuang ZY, Woolf CJ, Ji RR (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 23:4017–4022PubMedGoogle Scholar
  53. Kashiba H, Fukui H, Morikawa Y, Senba E (1999) Gene expression of histamine H1 receptor in guinea pig primary sensory neurons: a relationship between H1 receptor mRNA-expressing neurons and peptidergic neurons. Mol Brain Res 66:24–34PubMedGoogle Scholar
  54. Katsura H, Obata K, Mizushima T, Sakurai J, Kobayashi K, Yamanaka H, Dai Y, Fukuoka T, Sakagami M, Noguchi K (2006) Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury. J Neurosci 26:8680–8690PubMedGoogle Scholar
  55. Kerr BJ, Bradbury EJ, Bennett DL, Trivedi PM, Dassan P, French J, Shelton DB, McMahon SB, Thompson SW (1999) Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord. J Neurosci 19:5138–5148PubMedGoogle Scholar
  56. Kim SY, Bae JC, Kim JY, Lee HL, Lee KM, Kim DS, Cho HJ (2002) Activation of p38 MAP kinase in the rat dorsal root ganglia and spinal cord following peripheral inflammation and nerve injury. Neuroreport 13:2483–2486PubMedGoogle Scholar
  57. Koltzenburg M, Bennett DL, Shelton DL, McMahon SB (1999) Neutralization of endogenous NGF prevents the sensitization of nociceptors supplying inflamed skin. Eur J Neurosci 11:1698–1704PubMedGoogle Scholar
  58. Ledeboer A, Sloane EM, Milligan ED, Frank MG, Mahony JH, Maier SF, Watkins LR (2005) Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 115:71–83PubMedGoogle Scholar
  59. 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
  60. Lever IJ, Rice AS (2007) Cannabinoids and pain. Hadb Exp Pharmacol 177:265–306Google Scholar
  61. Levine JD, Gooding J, Donatoni P, Borden L, Goetzl EJ (1985) The role of the polymorphonuclear leukocyte in hyperalgesia. J Neurosci 5:3025–3029PubMedGoogle Scholar
  62. Lindenlaub T, Sommer C (2003) Cytokines in sural nerve biopsies from inflammatory and non-inflammatory neuropathies. Acta Neuropathol 105:593–602PubMedGoogle Scholar
  63. Lindenlaub T, Teuteberg P, Hartung T, Sommer C (2000) Effects of neutralizing antibodies to TNF-alpha on pain-related behavior and nerve regeneration in mice with chronic constriction injury. Brain Res 866:15–22PubMedGoogle Scholar
  64. Lindia JA, Kohler MG, Martin WJ, Abbadie C (2005) Relationship between sodium channel Nav1.3 expression and neuropathic pain behavior in rats. Pain 117:145–153PubMedGoogle Scholar
  65. Lindsay RM, Harmar AJ (1989) Nerve growth factor regulates expression of neuropeptide genes in adult sensory neurons. Nature 337:362–364PubMedGoogle Scholar
  66. Liu T, van Rooijen N, Tracey DJ (2000) Depletion of macrophages reduces axonal egeneration and hyperalgesia following nerve injury. Pain 86:25–32PubMedGoogle Scholar
  67. Liu XZ, Zhou JL, Chung KS, Chung JM (2001) Ion channels associated with the ectopic discharges generated after segmental spinal nerve injury in the rat. Brain Res 900:119–127PubMedGoogle Scholar
  68. Ma W, Quirion R (2005) The ERK/MAPK pathway, as a target for the treatment of neuropathic pain. Expert Opin Ther Targets 9:699–713PubMedGoogle Scholar
  69. Ma W, Quirion R (2006) Increased calcitonin gene-related peptide in neuroma and invading macrophages is involved in the up-regulation of interleukin-6 and thermal hyperalgesia in a rat model of mononeuropathy. J Neurochem 98:180–192PubMedGoogle Scholar
  70. Ma W, Quirion R (2007) Inflammatory mediators modulating the transient receptor potential vanilloid 1 receptor: therapeutic targets to treat inflammatory and neuropathic pain. Expert Opin Ther Targets 11:307–320Google Scholar
  71. Malcangio M, Lessmann V (2003) A common thread for pain and memory synapses? Brain-derived neurotrophic factor and trkB receptors. Trends Pharmacol Sci 24:116–121PubMedGoogle Scholar
  72. Mamet J, Lazdunski M, Voilley N (2003) How nerve growth factor drives physiological and inflammatory expressions of acid-sensing ion channel 3 in sensory neurons. J Biol Chem 278:48907–48913PubMedGoogle Scholar
  73. Marchand F, Perretti M, McMahon SB (2005) Role of the immune system in chronic pain. Nat Rev Neurosci 6:521–532Google Scholar
  74. Matthews EA, Dickenson AH (2001) Effects of spinally delivered N- and P-type voltage-dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of neuropathy. Pain 92:235–246PubMedGoogle Scholar
  75. McAllister AK, Katz LC, Lo DC (1999) Neurotrophins and synaptic plasticity. Annu Rev Neurosci 22:295–318PubMedGoogle Scholar
  76. McCleane GJ (1998) The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain. Anesth Analg 87:1117–1120PubMedGoogle Scholar
  77. McMahon SB, Bennett DL, Priestley JV, Shelton DL (1995) The biological effects of endogenous nerve growth factor on adult sensory neurons revealed by a trkA-IgG fusion molecule. Nat Med 1:774–780PubMedGoogle Scholar
  78. McQuay HJ, Tramer M, Nye BA, Carroll D, Wiffen PJ, Moore RA (1996) Systematic review of antidepressants in neuropathic pain. Pain 68:217–227PubMedGoogle Scholar
  79. Meller ST, Dykstra C, Grzybycki D, Murphy S, Gebhart GF (1994) The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat. Neuropharmacology 33:1471–1478PubMedGoogle Scholar
  80. Metcalfe DD, Baram D, Mekori YA (1997) Mast cells. Physiol Rev 77:1033–1079PubMedGoogle Scholar
  81. Michael GJ, Averill S, Nitkunan A, Rattray M, Bennett DL, Yan Q, Priestley JV (1997) Nerve growth factor treatment increases brain-derived neurotrophic factor selectively in TrkA-expressing dorsal root ganglion cells and in their central terminations within the spinal cord. J Neurosci 17:8476–8490PubMedGoogle Scholar
  82. 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 11:3539–3551PubMedGoogle Scholar
  83. Milligan ED, Mehmert KK, Hinde JL, Harvey LO, Martin D, Tracey KJ, Maier SF, Watkins LR (2000) Thermal hyperalgesia and mechanical allodynia produced by intrathecal administration of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein, gp120. Brain Res 861:105–116PubMedGoogle Scholar
  84. Milligan ED, Twining C, Chacur M, Biedenkapp J, O'Connor K, Poole S, Tracey K, Martin D, Maier SF, Watkins LR (2003) Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci 23:1026–1040PubMedGoogle Scholar
  85. Milligan ED, Langer SJ, Sloane EM, He L, Wieseler-Frank J, O'Connor K, Martin D, Forsayeth JR, Maier SF, Johnson K, Chavez RA, Leinwand LA, Watkins LR (2005) Controlling pathological pain by adenovirally driven spinal production of the anti-inflammatory cytokine, interleukin-10. Eur J Neurosci 21:2136–2148PubMedGoogle Scholar
  86. Munro G, Dalby-Brown W (2007) Kv7 (KCNQ) channel modulators and neuropathic pain. J Med Chem 50:2576–2582PubMedGoogle Scholar
  87. Myers RR, Heckman HM, Rodriguez M (1996) Reduced hyperalgesia in nerve-injured WLD mice: relationship to nerve fiber phagocytosis, axonal degeneration, and regeneration in normal mice. Exp Neurol 141:94–101PubMedGoogle Scholar
  88. Nassar MA, Levato A, Stirling LC, Wood JN (2005) Neuropathic pain develops normally in mice lacking both Nav1.7 and Nav1.8. Molecular Pain 1:24PubMedGoogle Scholar
  89. 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 2:33PubMedGoogle Scholar
  90. Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM (2004) Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 350:1104–1110PubMedGoogle Scholar
  91. Peng XM, Zhou ZG, Glorioso JC, Fink DJ, Mata M (2006) Tumor necrosis factor-alpha contributes to below-level neuropathic pain after spinal cord injury. Ann Neurol 59:843–851PubMedGoogle Scholar
  92. Perkins NM, Tracey DJ (2000) Hyperalgesia due to nerve injury: role of neutrophils. Neuroscience 101:745–757PubMedGoogle Scholar
  93. Perry VH, Brown MC, Gordon S (1987) The macrophage response to central and peripheral nerve injury. A possible role for macrophages in regeneration. J Exp Med 165:1218–1223Google Scholar
  94. Petty BG, Cornblath DR, Adornato BT, Chaudhry V, Flexner C, Wachsman M, Sinicropi D, Burton LE, Peroutka SJ (1994) The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann Neurol 36:244–246PubMedGoogle Scholar
  95. Pezet S, McMahon SB (2006) Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci 29:507–538PubMedGoogle Scholar
  96. Pezet S, Malcangio M, McMahon SB (2002b) BDNF: a neuromodulator in nociceptive pathways? Brain Res Brain Res Rev 40:240–249PubMedGoogle Scholar
  97. Pezet S, Malcangio M, Lever IJ, Perkinton MS, Thompson SW, Williams RJ, McMahon SB (2002a) Noxious stimulation induces Trk receptor and downstream ERK phosphorylation in spinal dorsal horn. Mol Cell Neurosci 21:684–695PubMedGoogle Scholar
  98. Raghavendra V, Tanga F, DeLeo JA (2003) Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 306:624–630PubMedGoogle Scholar
  99. Rasband MN, Park EW, Vanderah TW, Lai J, Porreca F, Trimmer JS (2001) Distinct potassium channels on pain-sensing neurons. Proc Natl Acad Sci USA 98:13373–13378Google Scholar
  100. Reeve AJ, Patel S, Fox A, Walker K, Urban L (2000) Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat. Eur J Pain 4:247–257PubMedGoogle Scholar
  101. Rice AS, Hill RG (2006) New treatments for neuropathic pain. Annu Rev Med 57:535–551PubMedGoogle Scholar
  102. Rueff A, Mendell LM (1996) Nerve growth factor NT-5 induce increased thermal sensitivity of cutaneous nociceptors in vitro. J Neurophysiol 76:3593–3596PubMedGoogle Scholar
  103. Rutkowski MD, Pahl JL, Sweitzer S, van Rooijen N, DeLeo JA (2000) Limited role of macrophages in generation of nerve injury-induced mechanical allodynia. Physiol Behav 71:225–235PubMedGoogle Scholar
  104. Rutkowski MD, Lambert F, Raghavendra V, Deleo JA (2004) Presence of spinal B7.2 (CD86) but not B7.1 (CD80) co-stimulatory molecules following peripheral nerve injury: role of nondestructive immunity in neuropathic pain. J Neuroimmunol 146:94–98PubMedGoogle Scholar
  105. Scapini P, Lapinet-Vera JA, Gasperini S, Calzetti F, Bazzoni F, Cassatella MA (2000) The neutrophil as a cellular source of chemokines. Immunol Rev 177:195–203PubMedGoogle Scholar
  106. Schafers M, Brinkhoff J, Neukirchen S, Marziniak M, Sommer C (2001) Combined epineurial therapy with neutralizing antibodies to tumor necrosis factor-alpha and interleukin-1 receptor has an additive effect in reducing neuropathic pain in mice. Neurosci Lett 310:113–116PubMedGoogle Scholar
  107. Schafers M, Geis C, Svensson CI, Luo ZD, Sommer C (2003a) Selective increase of tumour necrosis factor-alpha in injured and spared myelinated primary afferents after chronic constrictive injury of rat sciatic nerve. Eur J Neurosci 17:791–804PubMedGoogle Scholar
  108. Schafers M, Lee DH, Brors D, Yaksh TL, Sorkin LS (2003b) Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation. J Neurosci 23:3028–3038PubMedGoogle Scholar
  109. Schafers M, Svensson CI, Sommer C, Sorkin LS (2003c) Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci 23:2517–2521PubMedGoogle Scholar
  110. Shembalkar P, Taubel J, Abadias M, Arezina R, Hammond K, Anand P (2001) Cizolirtine citrate (E-4018) in the treatment of chronic neuropathic pain. Curr Med Res Opin 17:262–266PubMedGoogle Scholar
  111. Shi N, Pardridge WM (2000) Noninvasive gene targeting to the brain. Proc Natl Acad Sci USA 97:7567–7572PubMedGoogle Scholar
  112. Shu X, Mendell LM (1999) Nerve growth factor acutely sensitizes the response of adult rat sensory neurons to capsaicin. Neurosci Lett 274:159–162PubMedGoogle Scholar
  113. Sindrup SH, Jensen TS (1999) Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 83:389–400PubMedGoogle Scholar
  114. Sommer C, 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 784:154–162PubMedGoogle Scholar
  115. Sommer C, Marziniak M, Myers RR (1998) The effect of thalidomide treatment on vascular pathology and hyperalgesia caused by chronic constriction injury of rat nerve. Pain 74:83–91PubMedGoogle Scholar
  116. Sommer C, Lindenlaub T, Teuteberg P, Schafers M, Hartung T, Toyka KV (2001a) Anti-TNF-neutralizing antibodies reduce pain-related behavior in two different mouse models of painful mononeuropathy. Brain Res 913:86–89PubMedGoogle Scholar
  117. Sommer C, Schafers M, Marziniak M, Toyka KV (2001b) Etanercept reduces hyperalgesia in experimental painful neuropathy. J Peripher Nerv Syst 6:67–72PubMedGoogle Scholar
  118. Stucky CL, Koltzenburg M, Schneider M, Engle MG, Albers KM, Davis BM (1999) Overexpression of nerve growth factor in skin selectively affects the survival and functional properties of nociceptors. J Neurosci 19:8509–8516PubMedGoogle Scholar
  119. Sweitzer SM, Schubert P, Deleo JA (2001) Propentofylline, a glial modulating agent, exhibits antiallodynic properties in a rat model of neuropathic pain. J Pharmacol Exp Ther 297:1210–1217PubMedGoogle Scholar
  120. Sweitzer SM, Peters MC, Ma JY, Kerr I, Mangadu R, Chakravarty S, Dugar S, Medicherla S, Protter AA, Yeomans DC (2004) Peripheral and central p38 MAPK mediates capsaicin-induced hyperalgesia. Pain 111:278–285PubMedGoogle Scholar
  121. Tanaka T, Minami M, Nakagawa T, Satoh M (2004) Enhanced production of monocyte chemoattractant protein-1 in the dorsal root ganglia in a rat model of neuropathic pain: possible involvement in the development of neuropathic pain. Neurosci Res 48:463–469PubMedGoogle Scholar
  122. Thacker MA, Clark AK, Marchand F, McMahon SB (2007) Pathophysiology of peripheral neuropathic pain: immune cells and molecules. Anesth Analg 105:838–847PubMedGoogle Scholar
  123. Thompson SW, Bennett DL, Kerr BJ, Bradbury EJ, McMahon SB (1999) Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord. Proc Natl Acad Sci USA 96:7714–7718PubMedGoogle Scholar
  124. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, Hansson P, Hughes R, Nurmikko T, Serra J (2008) Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 70:1630–1635PubMedGoogle Scholar
  125. Tsuda M, Mizokoshi A, Shigemoto-Mogami Y, Koizumi S, Inoue K (2004) Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia 45:89–95PubMedGoogle Scholar
  126. Uceyler N, Rogausch JP, Toyka KV, Sommer C (2007) Differential expression of cytokines in painful and painless neuropathies. Neurology 69:42–49PubMedGoogle Scholar
  127. Velazquez KT, Mohammad H, Sweitzer SM (2007) Protein kinase C in pain: involvement of multiple isoforms. Pharmacol Res 55:578–589PubMedGoogle Scholar
  128. Wagner R, Myers RR (1996) Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. Neuroreport 7:2897–2901PubMedGoogle Scholar
  129. Wagner R, Myers RR, O'Brien JS (1998) Prosaptide prevents hyperalgesia and reduces peripheral TNFR1 expression following TNF-alpha nerve injection. Neuroreport 9:2827–2831PubMedGoogle Scholar
  130. Watkins LR, Maier SF (2003) Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2 973–985PubMedGoogle Scholar
  131. White FA, Sun J, Waters SM, Ma C, Ren D, Ripsch M, Steflik J, Cortright DN, LaMotte RH, Miller RJ (2005) Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. Proc Natl Acad Sci USA 102:14092–14097PubMedGoogle Scholar
  132. Wolfe D, Hao S, Hu J, Srinivasan R, Goss J, Mata M, Fink DJ, Glorioso JC (2007) Engineering an endomorphin-2 gene for use in neuropathic pain therapy. Pain 133:29–38PubMedGoogle Scholar
  133. Wood JN (2006) Molecular mechanisms of nociception and pain. Handb Clin Neurol 81:49–59PubMedGoogle Scholar
  134. Wood JN, Boorman J (2005) Voltage-gated sodium channel blockers: target validation and therapeutic potential. Curr Top Med Chem 5:529–537PubMedGoogle Scholar
  135. Woolf CJ, Safieh-Garabedian B, Ma QP, Crilly P, Winter J (1994) Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity. Neuroscience 62:327–331PubMedGoogle Scholar
  136. Xu J, Gingras KM, Bengston L, Di Marco A, Forger NG (2001) Blockade of endogenous neurotrophic factors prevents the androgenic rescue of rat spinal motoneurons. J Neurosci 21:4366–4372PubMedGoogle Scholar
  137. Xu JT, Tu HY, Xin WJ, Liu XG, Zhang GH, Zhai CH (2007) Activation of phosphatidylinositol 3-kinase and protein kinase B/Akt in dorsal root ganglia and spinal cord contributes to the neuropathic pain induced by spinal nerve ligation in rats. Exp Neurol 206:269–279PubMedGoogle Scholar
  138. Yaksh TL (2006) Calcium channels as therapeutic targets in neuropathic pain. J Pain 7:S13–S30PubMedGoogle Scholar
  139. Zelenka M, Schafers M, Sommer C (2005) Intraneural injection of interleukin-1[beta] and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain. Pain 116:257–263PubMedGoogle Scholar
  140. Zhang J, Shi XQ, Echeverry S, Mogil JS, De Koninck Y, Rivest S (2007) Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neurosci 27:12396–12406PubMedGoogle Scholar
  141. Zhou XF, Rush RA (1996) Endogenous brain-derived neurotrophic factor is anterogradely transported in primary sensory neurons. Neuroscience 74:945–953PubMedGoogle Scholar
  142. Zhou XF, Chie ET, Deng YS, Zhong JH, Xue Q, Rush RA, Xian CJ (1999) Injured primary sensory neurons switch phenotype for brain-derived neurotrophic factor in the rat. Neuroscience 92:841–853PubMedGoogle Scholar
  143. Zhuang ZY, Gerner P, Woolf CJ, Ji RR (2005) ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 114:149–159PubMedGoogle Scholar
  144. Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, Decosterd I, Ji RR (2006) A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 26:3551–3560PubMedGoogle Scholar
  145. Zuo Y, Perkins NM, Tracey DJ, Geczy CL (2003) Inflammation and hyperalgesia induced by nerve injury in the rat: a key role of mast cells. Pain 105:467–479PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Fabien March
    • 1
  • Nicholas G. Jones
    • 1
  • Stephen B. McMahon
    • 1
  1. 1.London Pain ConsortiumKing’s College LondonLondonUK

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