Neuropathic Pain: A Clinical Perspective

  • Ralf BaronEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 194)


Neuropathic pain syndromes, i.e., pain after a lesion or disease of the peripheral or central nervous system, are clinically characterized by spontaneous pain (ongoing, paroxysms) and evoked types of pain (hyperalgesia, allodynia). A variety of distinct pathophysiological mechanisms in the peripheral and central nervous system operate in concert: In some patients the nerve lesion triggers molecular changes in nociceptive neurons that become abnormally sensitive and develop pathological spontaneous activity (upregulation of sodium channels and receptors, e.g., vanilloid TRPV1 receptors, menthol-sensitive TRPM8 receptors, or α-receptors). These phenomena may lead to spontaneous pain, shooting pain sensations, as well as heat hyperalgesia, cold hyperalgesia, and sympathetically maintained pain. Spontaneous activity in damaged large nonnociceptive A-fibers may lead to paresthesias. All these changes may also occur in uninjured neurons driven by substances released by adjacent dying cells and should receive more attention in the future. The hyperactivity in nociceptors in turn induces secondary changes (hyperexcitability) in processing neurons in the spinal cord and brain. This central sensitization causes input from mechanoreceptive A-fibers to be perceived as pain (mechanical allodynia). Neuroplastic changes in the central descending pain modulatory systems (inhibitory or facilitatory) may lead to further hyperexcitability. Neuropathic pain represents a major neurological problem and treatment of patients with such pain has been largely neglected by neurologists in the past. The medical management of neuropathic pain consists of five main classes of oral medication (antidepressants with reuptake blocking effect, anticonvulsants with sodium-blocking action, anticonvulsants with calcium-modulating actions, tramadol, and opioids) and several categories of topical medications for patients with cutaneous allodynia and hyperalgesia (capsaicin and local anesthetics). In many cases an early combination of compounds effecting different mechanisms is useful. At present existing trials only provide general pain relief values for specific causes, which in part may explain the failure to obtain complete pain relief in neuropathic pain conditions. In general, the treatment of neuropathic pain is still unsatisfactorily. Therefore, a new hypothetical concept was proposed in which pain is analyzed on the basis of underlying mechanisms. The increased knowledge of pain-generating mechanisms and their translation into symptoms and signs may in the future allow a dissection of the mechanisms that operate in each patient. If a systematic clinical examination of the neuropathic pain patient and a precise phenotypic characterization is combined with a selection of drugs acting against those particular mechanisms, it should ultimately be possible to design optimal treatments for the individual patient.


Neuropathy Pathophysiology Assessment Treatment 



This work was supported by the Deutsche Forschungsgemeinschaft (DFG Ba 1921/1-2), the German Ministry of Research and Education within the German Research Network on Neuropathic Pain (BMBF, 01EM01/04), and an unrestricted educational grant from Pfizer (Germany).


  1. Alessandri-Haber N, Dina OA, Yeh JJ, Parada CA, Reichling DB, Levine JD (2004) Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. J Neurosci 24:4444–4452PubMedCrossRefGoogle Scholar
  2. Ali Z, Raja SN, Wesselmann U, Fuchs P, Meyer RA, Campbell JN (2000) Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain. Pain 88:161–168PubMedCrossRefGoogle Scholar
  3. Amir R, Liu CN, Kocsis JD, Devor M (2002) Oscillatory mechanism in primary sensory neurones. Brain 125:421–435PubMedCrossRefGoogle Scholar
  4. Baron R (2006) Mechanisms of disease: neuropathic pain – a clinical perspective. Nat Clin Pract Neurol 2:95–106PubMedCrossRefGoogle Scholar
  5. Baron R, Binder A (2004) How neuropathic is sciatica? The mixed pain concept. Orthopade 33:568–575PubMedCrossRefGoogle Scholar
  6. Baron R, Janig W (2004) Complex regional pain syndromes – how do we escape the diagnostic trap? Lancet 364:1739–1741PubMedCrossRefGoogle Scholar
  7. Baron R, Wasner G (2006) Prevention and treatment of postherpetic neuralgia. Lancet 367:186–188PubMedCrossRefGoogle Scholar
  8. Baron R, Baron Y, Disbrow E, Roberts TPL (1999a) Brain processing of capsaicin-induced secondary hyperalgesia: a functional MRI study. Neurology 53:548–557PubMedGoogle Scholar
  9. Baron R, Levine JD, Fields HL (1999b) Causalgia and reflex sympathetic dystrophy: does the sympathetic nervous system contribute to the generation of pain? Muscle Nerve 22:678–695PubMedCrossRefGoogle Scholar
  10. Baron R, Baron Y, Disbrow E, Roberts TPL (2000) Activation of the somatosensory cortex during Aß-fiber mediated hyperalgesia – a MSI study. Brain Res 871:75–82PubMedCrossRefGoogle Scholar
  11. Baron R, Schwarz K, Kleinert A, Schattschneider J, Wasner G (2001) Histamine-induced itch converts into pain in neuropathic hyperalgesia. Neuroreport 12:3475–3478PubMedCrossRefGoogle Scholar
  12. Baron R, Schattschneider J, Binder A, Siebrecht D, Wasner G (2002) Relation between sympathetic vasoconstrictor activity and pain and hyperalgesia in complex regional pain syndromes: a case-control study. Lancet 359:1655–1660PubMedCrossRefGoogle Scholar
  13. Binder A, Baron R (2007) Sodium channels in neuropathic pain – friend or foe? Nat Clin Pract Neurol 3:179PubMedCrossRefGoogle Scholar
  14. Binder A, Stengel M, Maag R, Wasner G, Schoch R, Moosig F, Schommer B, Baron R (2007) Pain in oxaliplatin-induced neuropathy – sensitisation in the peripheral and central nociceptive system. Eur J Cancer 43:2658–2663PubMedCrossRefGoogle Scholar
  15. Campbell JN, Raja SN, Meyer RA, Mackinnon SE (1988) Myelinated afferents signal the hyperalgesia associated with nerve injury. Pain 32:89–94PubMedCrossRefGoogle Scholar
  16. Catarina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313CrossRefGoogle Scholar
  17. Choi B, Rowbotham MC (1997) Effect of adrenergic receptor activation on post-herpetic neuralgia pain and sensory disturbances. Pain 69:55–63PubMedCrossRefGoogle Scholar
  18. Coull JA, Boudreau D, Bachand K, Prescott SA, Nault F, Sik A, De Koninck P, De Koninck Y (2003) Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424:938–942PubMedCrossRefGoogle Scholar
  19. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021PubMedCrossRefGoogle 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 444:894–898PubMedCrossRefGoogle Scholar
  21. Dib-Hajj SD, Rush AM, Cummins TR, Hisama FM, Novella S, Tyrrell L, Marshall L, Waxman SG (2005) Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Brain 128:1847–1854PubMedCrossRefGoogle Scholar
  22. Dworkin RH, Schmader KE (2003) Treatment and prevention of postherpetic neuralgia. Clin Infect Dis 36:877–882PubMedCrossRefGoogle Scholar
  23. Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, Bushnell MC, Farrar JT, Galer BS, Haythornthwaite JA, Hewitt DJ, Loeser JD, Max MB, Saltarelli M, Schmader KE, Stein C, Thompson D, Turk DC, Wallace MS, Watkins LR, Weinstein SM (2003) Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 60:1524–1534PubMedCrossRefGoogle Scholar
  24. Dworkin RH, O'Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy RK, Rice AS, Stacey BR, Treede RD, Turk DC, Wallace MS (2007) Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132:237–251PubMedCrossRefGoogle Scholar
  25. Fields HL, Rowbotham M, Baron R (1998) Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 5:209–227PubMedCrossRefGoogle Scholar
  26. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH (2005) Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 118:289–305PubMedCrossRefGoogle Scholar
  27. 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
  28. Freynhagen R, Rolke R, Baron R, Tolle TR, Rutjes AK, Schu S, Treede RD (2007) Pseudoradicular and radicular low-back pain – a disease continuum rather than different entities? Answers from quantitative sensory testing. Pain 135:65–74PubMedCrossRefGoogle Scholar
  29. Goldberg YP, MacFarlane J, MacDonald ML, Thompson J, Dube MP, Mattice M, Fraser R, Young C, Hossain S, Pape T, Payne B, Radomski C, Donaldson G, Ives E, Cox J, Younghusband HB, Green R, Duff A, Boltshauser E, Grinspan GA, Dimon JH, Sibley BG, Andria G, Toscano E, Kerdraon J, Bowsher D, Pimstone SN, Samuels ME, Sherrington R, Hayden MR (2007) Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet 71:311–319PubMedCrossRefGoogle Scholar
  30. Gracely RH, Lynch SA, Bennett GJ (1992) Painful neuropathy: altered central processing maintained dynamically by peripheral input. Pain 51:175–194. Erratum (1993) Pain 52: 251–253Google Scholar
  31. Guilbaud G, Benoist JM, Levante A, Gautron M, Willer JC (1992) Primary somatosensory cortex in rats with pain-related behaviours due to a peripheral mononeuropathy after moderate ligation of one sciatic nerve: neuronal responsivity to somatic stimulation. Exp Brain Res 92:227–245PubMedCrossRefGoogle Scholar
  32. Habler HJ, Janig W, Koltzenburg M (1987) Activation of unmyelinated afferents in chronically lesioned nerves by adrenaline and excitation of sympathetic efferents in the cat. Neurosci Lett 82:35–40PubMedCrossRefGoogle Scholar
  33. 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 24:4832–4839PubMedCrossRefGoogle Scholar
  34. Herrmann DN, Pannoni V, Barbano RL, Pennella-Vaughan J, Dworkin RH (2006) Skin biopsy and quantitative sensory testing do not predict response to lidocaine patch in painful neuropathies. Muscle Nerve 33:42–48PubMedCrossRefGoogle Scholar
  35. Hong S, Wiley JW (2005) Early painful diabetic neuropathy is associated with differential changes in the expression and function of vanilloid receptor 1. J Biol Chem 280:618–627PubMedGoogle Scholar
  36. Hudson LJ, Bevan S, Wotherspoon G, Gentry C, Fox A, Winter J (2001) VR1 protein expression increases in undamaged DRG neurons after partial nerve injury. Eur J Neurosci 13:2105–2114PubMedCrossRefGoogle Scholar
  37. Jacobs JM, Macfarlane RM, Cavanagh JB (1976) Vascular leakage in the dorsal root ganglia of the rat, studied with horseradish peroxidase. J Neurol Sci 29:95–107PubMedCrossRefGoogle Scholar
  38. Janig W, Baron R (2003) Complex regional pain syndrome: mystery explained? Lancet Neurol 2:687–697PubMedCrossRefGoogle Scholar
  39. Jensen TS, Baron R (2003) Translation of symptoms and signs into mechanisms in neuropathic pain. Pain 102:1–8PubMedCrossRefGoogle Scholar
  40. Ji RR, Woolf CJ (2001) Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis 8:1–10PubMedCrossRefGoogle Scholar
  41. 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
  42. Lai J, Hunter JC, Porreca F (2003) The role of voltage-gated sodium channels in neuropathic pain. Curr Opin Neurobiol 13:291–297PubMedCrossRefGoogle Scholar
  43. Lehky TJ, Leonard GD, Wilson RH, Grem JL, Floeter MK (2004) Oxaliplatin-induced neurotoxicity: acute hyperexcitability and chronic neuropathy. Muscle Nerve 29:387–392PubMedCrossRefGoogle Scholar
  44. Leijon G, Boivie J, Johansson I (1989) Central post-stroke pain – neurological symptoms and pain characteristics. Pain 36:13–25PubMedCrossRefGoogle Scholar
  45. Lindblom U, Verrillo RT (1979) Sensory functions in chronic neuralgia. J Neurol Neurosurg Psychiatr 42:422–435PubMedCrossRefGoogle Scholar
  46. Luo ZD, Chaplan SR, Higuera ES, Sorkin LS, Stauderman KA, Williams ME, Yaksh TL (2001) Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci 21:1868–1875PubMedGoogle Scholar
  47. Ma W, Zhang Y, Bantel C, Eisenach JC (2005) Medium and large injured dorsal root ganglion cells increase TRPV-1, accompanied by increased alpha2C-adrenoceptor co-expression and functional inhibition by clonidine. Pain 113:386–394PubMedCrossRefGoogle Scholar
  48. Maihofner C, Handwerker HO, Neundorfer B, Birklein F (2004) Cortical reorganization during recovery from complex regional pain syndrome. Neurology 63:693–701PubMedGoogle Scholar
  49. Maihofner C, Forster C, Birklein F, Neundorfer B, Handwerker HO (2005) Brain processing during mechanical hyperalgesia in complex regional pain syndrome: a functional MRI study. Pain 114:93–103PubMedCrossRefGoogle Scholar
  50. McKemy DD, Neuhausser WM, Julius D (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416:52–58PubMedCrossRefGoogle Scholar
  51. McQuay H, Carroll D, Jadad AR, Wiffen P, Moore A (1995) Anticonvulsant drugs for management of pain: a systematic review. BMJ 311:1047–1052PubMedGoogle Scholar
  52. McQuay HJ, Tramer M, Nye BA, Carroll D, Wiffen PJ, Moore RA (1996) A systematic review of antidepressants in neuropathic pain. Pain 68:217–227PubMedCrossRefGoogle Scholar
  53. Mogil JS, Miermeister F, Seifert F, Strasburg K, Zimmermann K, Reinold H, Austin JS, Bernardini N, Chesler EJ, Hofmann HA, Hordo C, Messlinger K, Nemmani KV, Rankin AL, Ritchie J, Siegling A, Smith SB, Sotocinal S, Vater A, Lehto SG, Klussmann S, Quirion R, Michaelis M, Devor M, Reeh PW (2005) Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene. Proc Natl Acad Sci USA 102:12938–12943PubMedCrossRefGoogle Scholar
  54. Moore KA, Kohno T, Karchewski LA, Scholz J, Baba H, Woolf CJ (2002) Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J Neurosci 22:6724–6731PubMedGoogle Scholar
  55. Nystrom B, Hagbarth KE (1981) Microelectrode recordings from transected nerves in amputees with phantom limb pain. Neurosci Lett 27:211–216PubMedCrossRefGoogle Scholar
  56. Obata K, Katsura H, Mizushima T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Tokunaga A, Tominaga M, Noguchi K (2005) TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. J Clin Invest 115:2393–2401PubMedCrossRefGoogle Scholar
  57. Ochoa JL, Yarnitsky D (1993) Mechanical hyperalgesias in neuropathic pain patients: dynamic and static subtypes. Ann Neurol 33:465–472PubMedCrossRefGoogle Scholar
  58. Omana-Zapata I, Khabbaz MA, Hunter JC, Clarke DE, Bley KR (1997) Tetrodotoxin inhibits neuropathic ectopic activity in neuromas, dorsal root ganglia and dorsal horn neurons. Pain 72:41–49PubMedCrossRefGoogle Scholar
  59. Orstavik K, Weidner C, Schmidt R, Schmelz M, Hilliges M, Jorum E, Handwerker H, Torebjork E (2003) Pathological C-fibres in patients with a chronic painful condition. Brain 126:567–578PubMedCrossRefGoogle Scholar
  60. Ossipov MH, Lai J, Malan TP Jr, Porreca F (2000) Spinal and supraspinal mechanisms of neuropathic pain. Ann N Y Acad Sci 909:12–24PubMedCrossRefGoogle Scholar
  61. Pappagallo M, Oaklander AL, Quatrano-Piacentini AL, Clark MR, Raja SN (2000) Heterogenous patterns of sensory dysfunction in postherpetic neuralgia suggest multiple pathophysiologic mechanisms. Anesthesiology 92:691–698PubMedCrossRefGoogle Scholar
  62. Patapoutian A, Peier AM, Story GM, Viswanath V (2003) ThermoTRP channels and beyond: mechanisms of temperature sensation. Nat Rev Neurosci 4:529–539PubMedCrossRefGoogle Scholar
  63. Petersen KL, Fields HL, Brennum J, Sandroni P, Rowbotham MC (2000) Capsaicin evoked pain and allodynia in post-herpetic neuralgia. Pain 88:125–133PubMedCrossRefGoogle Scholar
  64. Pleger B, Tegenthoff M, Schwenkreis P, Janssen F, Ragert P, Dinse HR, Volker B, Zenz M, Maier C (2004) Mean sustained pain levels are linked to hemispherical side-to-side differences of primary somatosensory cortex in the complex regional pain syndrome I. Exp Brain Res 155:115–119PubMedCrossRefGoogle Scholar
  65. Pleger B, Tegenthoff M, Ragert P, Forster AF, Dinse HR, Schwenkreis P, Nicolas V, Maier C (2005) Sensorimotor retuning [corrected] in complex regional pain syndrome parallels pain reduction. Ann Neurol 57:425–429PubMedCrossRefGoogle Scholar
  66. Price DD, Long S, Huitt C (1992) Sensory testing of pathophysiological mechanisms of pain in patients with reflex sympathetic dystrophy. Pain 49:163–173PubMedCrossRefGoogle Scholar
  67. Price DD, Long S, Wilsey B, Rafii A (1998) Analysis of peak magnitude and duration of analgesia produced by local anesthetics injected into sympathetic ganglia of complex regional pain syndrome patients. Clin J Pain 14:216–226PubMedCrossRefGoogle Scholar
  68. Raja SN, Abatzis V, Frank SM (1998) Role of a-adrenoceptors in neuroma pain in amputees. Anesthesiology 89:A1083CrossRefGoogle Scholar
  69. Raja SN, Haythornthwaite JA, Pappagallo M, Clark MR, Travison TG, Sabeen S, Royall RM, Max MB (2002) Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 59:1015–1021PubMedGoogle Scholar
  70. Rolke R, Baron R, Maier C, Tolle TR, Treede RD, Beyer A, Binder A, Birbaumer N, Birklein F, Botefur IC, Braune S, Flor H, Huge V, Klug R, Landwehrmeyer GB, Magerl W, Maihofner C, Rolko C, Schaub C, Scherens A, Sprenger T, Valet M, Wasserka B (2006) Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 123:231–43PubMedCrossRefGoogle Scholar
  71. Rowbotham MC, Fields HL (1996) The relationship of pain, allodynia and thermal sensation in post-herpetic neuralgia. Brain 119:347–354PubMedCrossRefGoogle Scholar
  72. Rowbotham MC, Yosipovitch G, Connolly MK, Finlay D, Forde G, Fields HL (1996) Cutaneous innervation density in the allodynic form of postherpetic neuralgia. Neurobiol Dis 3:205–214PubMedCrossRefGoogle Scholar
  73. Sato J, Perl ER (1991) Adrenergic excitation of cutaneous pain receptors induced by peripheral nerve injury. Science 251:1608–1610PubMedCrossRefGoogle Scholar
  74. Schattschneider J, Scarano M, Binder A, Wasner G, Baron R (2007) Modulation of sensitized C-fibers by adrenergic stimulation in human neuropathic pain. Eur J Pain 12:517–524PubMedCrossRefGoogle Scholar
  75. Siddall PJ, Middleton JW (2006) A proposed algorithm for the management of pain following spinal cord injury. Spinal Cord 44:67–77PubMedCrossRefGoogle Scholar
  76. Sindrup SH, Jensen TS (1999) Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 83:389–400PubMedCrossRefGoogle Scholar
  77. Sindrup SH, Jensen TS (2000) Pharmacologic treatment of pain in polyneuropathy. Neurology 55:915–920PubMedGoogle Scholar
  78. Tal M, Bennett GJ (1994) Extra-territorial pain in rats with a peripheral mononeuropathy: mechano-hyperalgesia and mechano-allodynia in the territory of an uninjured nerve. Pain 57:375–382PubMedCrossRefGoogle Scholar
  79. Torebjork E, Wahren L, Wallin G, Hallin R, Koltzenburg M (1995) Noradrenaline-evoked pain in neuralgia. Pain 63:11–20PubMedCrossRefGoogle Scholar
  80. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, Hansson P, Hughes R, Nurmikko T, Serra J (2007) Neuropathic pain. Redefinition and a grading system for clinical and research purposes. Neurology 70:1630–1635PubMedCrossRefGoogle Scholar
  81. Vanegas H, Schaible HG (2004) Descending control of persistent pain: inhibitory or facilitatory? Brain Res Brain Res Rev 46:295–309PubMedCrossRefGoogle Scholar
  82. Wasner G, Schattschneider J, Binder A, Baron R (2004) Topical menthol – a human model for cold pain by activation and sensitization of C nociceptors. Brain 127:1159–1171PubMedCrossRefGoogle Scholar
  83. Wasner G, Kleinert A, Binder A, Schattschneider J, Baron R (2005) Postherpetic neuralgia: topical lidocaine is effective in nociceptor-deprived skin. J Neurol 252:677–686PubMedCrossRefGoogle Scholar
  84. Wieseler-Frank J, Maier SF, Watkins LR (2005) Immune-to-brain communication dynamically modulates pain: physiological and pathological consequences. Brain Behav Immun 19:104–111PubMedCrossRefGoogle Scholar
  85. Willoch F, Schindler F, Wester HJ, Empl M, Straube A, Schwaiger M, Conrad B, Tolle TR (2004) Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C]diprenorphine PET study. Pain 108:213–220PubMedCrossRefGoogle Scholar
  86. Wood JN, Boorman JP, Okuse K, Baker MD (2004) Voltage-gated sodium channels and pain pathways. J Neurobiol 61:55–71PubMedCrossRefGoogle Scholar
  87. Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, Lipton R, Loeser JD, Payne R, Torebjork E (1998) Towards a mechanism-based classification of pain? Pain 77:227–229PubMedCrossRefGoogle Scholar
  88. Wu G, Ringkamp M, Hartke TV, Murinson BB, Campbell JN, Griffin JW, Meyer RA (2001) Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers. J Neurosci 21:RC140PubMedGoogle Scholar
  89. Xing H, Chen M, Ling J, Tan W, Gu JG (2007) TRPM8 mechanism of cold allodynia after chronic nerve injury. J Neurosci 27:13680–13690PubMedCrossRefGoogle Scholar
  90. Zambreanu L, Wise RG, Brooks JC, Iannetti GD, Tracey I (2005) A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging. Pain 114:397–407Google Scholar

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© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  1. 1.Sektion Neurologische Schmerzforschung und Therapie, Klinik für NeurologieChristian-Albrechts-Universität KielKielGermany

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