Neural Basis of Pain in Herpes Zoster and Postherpetic Neuralgia: The Ectopic Pacemaker Hypothesis

  • Marshall DevorEmail author


Pain in herpes zoster and postherpetic neuralgia is classically ascribed to irritable, inflammation-sensitized nociceptors in the cutaneous rash and to spinal cord deafferentation. After considering weaknesses in the evidence base underlying this view an alternative explanation is offered, based on hyperexcitability at ectopic pacemaker sites in affected primary sensory neurons, and central sensitization induced and maintained by the ectopic activity.



I wish to thank the following individuals for their helpful responses to queries about unpublished observations concerning herpes zoster and postherpetic neuralgia, and for their guidance on published material: Ralf Baron, Shane Brogan, Perry Fine, Ron Goldstein, Michaela Kress, John Loeser, Florella Magora, Christof Maier, Turo Nurmikko, Anne Louise Oaklander, Gabor Racz, Srinivasa Raja, Zvi Harry Rappaport, Andrew Rice, Michael Rowbotham, Ze’ev Seltzer, Jordi Serra, Claudia Sommer, Maarten van Kleef, and Bart van Wijck. A special note of thanks is due to Peter Watson for his feedback on numerous factual and conceptual issues related to the text. The authors’ research on neuropathic pain mechanisms is funded by the Israel Science Foundation, the Seymour and Cecile Alpert Chair in Pain Research, and the Hebrew University Center for Research on Pain.


  1. 1.
    Ahmed SU, Zhang Y, Chen L, Cohen A, St Hillary K, Vo T, Houghton M, Mao J (2015) Effect of 1.5 % topical diclofenac on clinical neuropathic pain. Anesthesiology 123:191–198PubMedCrossRefGoogle Scholar
  2. 2.
    Ali Z, Ringkamp M, Hartke TV, Chien HF, Flavahan NA, Campbell JN, Meyer R (1999) Uninjured cutaneous C-fiber nociceptors develop spontaneous activity and alpha adrenergic sensitivity following L6 spinal nerve ligation in the monkey. J Neurophysiol 81:455–466PubMedCrossRefGoogle Scholar
  3. 3.
    Amir R, Michaelis M, Devor M (2002) Burst discharge in primary sensory neurons: triggered by subthreshold oscillations, maintained by depolarizing afterpotentials. J Neurosci 22:1187–1198PubMedCrossRefGoogle Scholar
  4. 4.
    Andrew D, Greenspan JD (1999) Mechanical and heat sensitization of cutaneous nociceptors after peripheral inflammation in the rat. J Neurophysiol 82:2649–2656PubMedCrossRefGoogle Scholar
  5. 5.
    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
  6. 6.
    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 138:380–391PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Bouhassira D, Attal N, Alchaar H, Boureau F, Brochet B, Bruxelle J, Cunin G, Fermanian J, Ginies P, Grun-Overdyking A, Jafari-Schluep H, Lanteri-Minet M, Laurent B, Mick G, Serrie A, Valade D, Vicaut E (2005) Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 114:29–36PubMedCrossRefGoogle Scholar
  8. 8.
    Browder J, de Veer JA (1949) Herpes zoster: a surgical procedure for the treatment of postherpetic neuralgia. Ann Surg 130:622–635PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Buonocore M, Gatti AM, Amato G, Aloisi AM, Bonezzi C (2012) Allodynic skin in post-herpetic neuralgia: histological correlates. J Cell Physiol 227:934–938PubMedCrossRefGoogle Scholar
  10. 10.
    Burchiel KJ (2015) Surgical management of pain, 2nd edn. Thieme, New York, p. 631Google Scholar
  11. 11.
    Campbell CM, Diamond E, Schmidt WK, Kelly M, Allen R, Houghton W, Brady KL, Campbell JN (2016) A randomized, double-blind, placebo-controlled trial of injected capsaicin for pain in Morton’s neuroma. Pain 157:1297–1304CrossRefGoogle Scholar
  12. 12.
    Campbell JN, Raja SN, Meyer RA, MacKinnon SE (1988) Myelinated afferents signal the hyperalgesia associated with nerve injury. Pain 32:89–94PubMedCrossRefGoogle Scholar
  13. 13.
    Campero M, Serra J, Marchettini P, Ochoa JL (1998) Ectopic impulse generation and autoexcitation in single myelinated afferent fibers in patients with peripheral neuropathy and positive sensory symptoms. Muscle Nerve 21:1661–1667PubMedCrossRefGoogle Scholar
  14. 14.
    Catterall WA (1987) Common modes of drug action on Na+ channels: local anaesthetics, antiarrhythmics and anticonvulsants. Trends Pharmacol Sci 8:57–65CrossRefGoogle Scholar
  15. 15.
    Chen N, Yang M, He L, Zhang D, Zhou M, Zhu C (2010) Corticosteroids for preventing postherpetic neuralgia. Cochrane Database Syst Rev 3:CD005582Google Scholar
  16. 16.
    Cohen JI (2013) Herpes zoster. N Engl J Med 369:1766–1767PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Cole NL, Grose C (2003) Membrane fusion mediated by herpesvirus glycoproteins: the paradigm of varicella-zoster virus. Rev Med Virol 13:207–222PubMedCrossRefGoogle Scholar
  18. 18.
    Defrin R, Devor M, Brill S (2014) Tactile allodynia in patients with lumbar radicular pain (sciatica). Pain 155(12):2551–2559PubMedCrossRefGoogle Scholar
  19. 19.
    Derry S, Sven-Rice A, Cole P, Tan T, Moore RA (2013) Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2:CD007393Google Scholar
  20. 20.
    Derry S, Wiffen PJ, Moore RA, Quinlan J (2014) Topical lidocaine for neuropathic pain in adults. Cochrane Database Syst Rev 7:CD010958Google Scholar
  21. 21.
    Devor M (1999) Unexplained peculiarities of the dorsal root ganglion. Pain suppl.6:S27–S35PubMedCrossRefGoogle Scholar
  22. 22.
    Devor M (2009) Ectopic discharge in Abeta afferents as a source of neuropathic pain. Exp Brain Res 196:115–128PubMedCrossRefGoogle Scholar
  23. 23.
    Devor M (2013) Neuropathic pain: pathophysiological response of nerves to injury. Chapter 61. In: McMahon SL, Koltzenburg M, Tracey I, Turk DC (eds) Wall and Melzack’s textbook of pain, 6th edn. Churchill Livingstone, London, pp. 861–888Google Scholar
  24. 24.
    Devor M, Basbaum A, Bennett G, Blumberg H, Campbell J, Dembowsky K, Guilbaud G, Janig W, Koltzenberg M, Levine J, Otten U, Portenoy R (1991) Mechanisms of neuropathic pain following peripheral injury. In: Basbaum A, Besson J-M (eds) Towards a new pharmacology of pain. Dahlem Konferenzen. Wiley, Chichester, pp. 417–440Google Scholar
  25. 25.
    Devor M, Govrin-Lippmann R (1991) Neurogenesis in adult rat dorsal root ganglia: on counting and the count. Somatosens Motor Res 8:9–12CrossRefGoogle Scholar
  26. 26.
    Devor M, Janig W (1981) Activation of myelinated afferents ending in a neuroma by stimulation of the sympathetic supply in the rat. Neurosci Lett 24:43–47PubMedCrossRefGoogle Scholar
  27. 27.
    Devor M, Keller CH, Deerinck T, Levinson SR, Ellisman MH (1989) Na+ channel accumulation on axolemma of afferents in nerve end neuromas in Apteronotus. Neurosci Lett 102:149–154PubMedCrossRefGoogle Scholar
  28. 28.
    Devor M, Wall PD, Catalan N (1992a) Systemic lidocaine silences ectopic neuroma and DRG discharge without blocking nerve conduction. Pain 48:261–268PubMedCrossRefGoogle Scholar
  29. 29.
    Devor M, White DM, Goetzl EJ, Levine JD (1992b) Eicosanoids, but not tachykinins, excite C-fiber endings in rat sciatic nerve-end neuromas. Neuroreport 3:21–24PubMedCrossRefGoogle Scholar
  30. 30.
    Dworkin RH, Johnson RW, Breuer J, Gnann JW, Levin MJ, Backonja M, Betts RF, Gershon AA, Haanpaa ML, McKendrick MW, Nurmikko TJ, Oaklander AL, Oxman MN, Pavan-Langston D, Petersen KL, Rowbotham MC, Schmader KE, Stacey BR, Tyring SK, van Wijck AJ, Wallace MS, Wassilew SW, Whitley RJ (2007) Recommendations for the management of herpes zoster. Clin Infect Dis 44(Suppl 1):S1–26PubMedCrossRefGoogle Scholar
  31. 31.
    Dworkin RH, O'Connor AB, Kent J, Mackey SC, Raja SN, Stacey BR, Levy RM, Backonja M, Baron R, Harke H, Loeser JD, Treede RD, Turk DC, Wells CD (2013) Interventional management of neuropathic pain: NeuPSIG recommendations. Pain 154:2249–2261PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    England JD, Happel LT, Kline DG, Gamboni F, Thouron CL, Liu ZP, Levinson SR (1996) Sodium channel accumulation in humans with painful neuromas. Neurology 47:272–276PubMedCrossRefGoogle Scholar
  33. 33.
    Fields HL, Rowbotham M, Baron R (1998) Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 5:209–227PubMedCrossRefGoogle Scholar
  34. 34.
    Filipovic B, Matak I, Bach-Rojecky L, Lackovic Z (2012) Central action of peripherally applied botulinum toxin type A on pain and dural protein extravasation in rat model of trigeminal neuropathy. PLoS One 7:e29803PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpaa M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M (2015) Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14:162–173PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Fleetwood-Walker SM, Quinn JP, Wallace C, Blackburn-Munro G, Kelly BG, Fiskerstrand CE, Nash AA, Dalziel RG (1999) Behavioural changes in the rat following infection with varicella-zoster virus. J Gen Virol 80(Pt 9):2433–2436PubMedCrossRefGoogle Scholar
  37. 37.
    Forbes HJ, Thomas SL, Smeeth L, Clayton T, Farmer R, Bhaskaran K, Langan SM (2016) A systematic review and meta-analysis of risk factors for postherpetic neuralgia. Pain 157:30–54CrossRefGoogle Scholar
  38. 38.
    Galer BS, Jensen MP, Ma T, Davies PS, Rowbotham MC (2002) The lidocaine patch 5 % effectively treats all neuropathic pain qualities: results of a randomized, double-blind, vehicle-controlled, 3-week efficacy study with use of the neuropathic pain scale. Clin J Pain 18:297–301PubMedCrossRefGoogle Scholar
  39. 39.
    Galluzzi KE (2009) Managing herpes zoster and postherpetic neuralgia. J Am Osteopath Assoc 109:S7–12PubMedGoogle Scholar
  40. 40.
    Gande AV, Chivukula S, Moossy JJ, Rothfus W, Agarwal V, Horowitz MB, Gardner PA (2016) Long-term outcomes of intradural cervical dorsal root rhizotomy for refractory occipital neuralgia. J Neurosurg 125:102–110CrossRefGoogle Scholar
  41. 41.
    Garry EM, Delaney A, Anderson HA, Sirinathsinghji EC, Clapp RH, Martin WJ, Kinchington PR, Krah DL, Abbadie C, Fleetwood-Walker SM (2005) Varicella zoster virus induces neuropathic changes in rat dorsal root ganglia and behavioral reflex sensitisation that is attenuated by gabapentin or sodium channel blocking drugs. Pain 118:97–111PubMedCrossRefGoogle Scholar
  42. 42.
    Gibson SJ, McGregor G, Bloom SR, Polak JM, Wall PD (1982) Local application of capsaicin to one sciatic nerve of the adult rat induces a marked depletion in the peptide content of the lumbar dorsal horn. Neuroscience 7:3153–3162PubMedCrossRefGoogle Scholar
  43. 43.
    Gibson SJ, Polak JM, Bloom SR, Sabate IM, Mulderry PM, Ghatei MA, McGregor GP, Morrison JF, Kelly JS, Evans RM et al (1984) Calcitonin gene-related peptide immunoreactivity in the spinal cord of man and of eight other species. J Neurosci 4:3101–3111PubMedCrossRefGoogle Scholar
  44. 44.
    Gracely R, Lynch S, Bennett G (1992) Painful neuropathy: altered central processing, maintained dynamically by peripheral input. Pain 51:175–194PubMedCrossRefGoogle Scholar
  45. 45.
    Greenberg SA (2003) The history of dermatome mapping. Arch Neurol 60:126–131PubMedCrossRefGoogle Scholar
  46. 46.
    Guedon JM, Yee MB, Zhang M, Harvey SA, Goins WF, Kinchington PR (2015) Neuronal changes induced by Varicella Zoster Virus in a rat model of postherpetic neuralgia. Virology 482:167–180PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Hanani M (2012) Intercellular communication in sensory ganglia by purinergic receptors and gap junctions: implications for chronic pain. Brain Res 1487:183–191PubMedCrossRefGoogle Scholar
  48. 48.
    Hardy JD, Wolf HG, Goodell H (1952) Pain sensations and reactions. William and Wilkins, New YorkGoogle Scholar
  49. 49.
    Haroutounian S, Nikolajsen L, Bendtsen TF, Finnerup NB, Kristensen AD, Hasselstrom JB, Jensen TS (2014) Primary afferent input critical for maintaining spontaneous pain in peripheral neuropathy. Pain 155:1272–1279PubMedCrossRefGoogle Scholar
  50. 50.
    Head H, Campbell AW (1900) The pathology of herpes zoster and its bearing on sensory localization. Brain 23:353–523CrossRefGoogle Scholar
  51. 51.
    Hempenstall K, Nurmikko TJ, Johnson RW, A'Hern RP, Rice AS (2005) Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med 2:e164PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Hou Q, Barr T, Gee L, Vickers J, Wymer J, Borsani E, Rodella L, Getsios S, Burdo T, Eisenberg E, Guha U, Lavker R, Kessler J, Chittur S, Fiorino D, Rice F, Albrecht P (2011) Keratinocyte expression of calcitonin gene-related peptide beta: implications for neuropathic and inflammatory pain mechanisms. Pain 152:2036–2051PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Johnson RW (2007) Zoster-associated pain: what is known, who is at risk and how can it be managed? Herpes 14(Suppl 2):30–34PubMedGoogle Scholar
  54. 54.
    Jones MJ, Murrin KR (1987) Intercostal block with cryotherapy. Ann R Coll Surg Engl 69:261–262PubMedPubMedCentralGoogle Scholar
  55. 55.
    Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413:203–210PubMedCrossRefGoogle Scholar
  56. 56.
    Kanpolat Y, Tuna H, Bozkurt M, Elhan AH (2008) Spinal and nucleus caudalis dorsal root entry zone operations for chronic pain. Neurosurgery 62:235–242 discussion 242-234PubMedGoogle Scholar
  57. 57.
    Kennedy PG, Montague P, Scott F, Grinfeld E, Ashrafi GH, Breuer J, Rowan EG (2013) Varicella-zoster viruses associated with post-herpetic neuralgia induce sodium current density increases in the ND7-23 Nav-1.8 neuroblastoma cell line. PLoS One 8:e51570PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kibler RF, Nathan PW (1960) Relief of pain and paraesthesiae by nerve block distal to a lesion. J Neurol Neurosurg Psychiatry 23:91–98PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Kinchington PR, Goins WF (2011) Varicella zoster virus-induced pain and post-herpetic neuralgia in the human host and in rodent animal models. J Neurovirol 17:590–599PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Kirk EJ, Denny-Brown D (1970) Functional variation in dermatomes in the macaque monkey following dorsal root lesions. J Comp Neurol 139:307–320PubMedCrossRefGoogle Scholar
  61. 61.
    Kleggetveit IP, Namer B, Schmidt R, Helas T, Ruckel M, Orstavik K, Schmelz M, Jorum E (2012) High spontaneous activity of C-nociceptors in painful polyneuropathy. Pain 153:2040–2047PubMedCrossRefGoogle Scholar
  62. 62.
    Kocher L, Anton F, Reeh PW, Handwerker HO (1987) The effect of carrageenan-induced inflammation on the sensitivity of unmyelinated skin nociceptors in the rat. Pain 29:363–373PubMedCrossRefGoogle Scholar
  63. 63.
    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
  64. 64.
    Koltzenburg M, Kress M, Reeh PW (1992) The nociceptor sensitization by bradykinin does not depend on sympathetic neurons. Neuroscience 46:465–473PubMedCrossRefGoogle Scholar
  65. 65.
    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
  66. 66.
    Kotani N, Kushikata T, Hashimoto H, Kimura F, Muraoka M, Yodono M, Asai M, Matsuki A (2000) Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 343:1514–1519PubMedCrossRefGoogle Scholar
  67. 67.
    Kress M, Fickenscher H (2001) Infection by human varicella-zoster virus confers norepinephrine sensitivity to sensory neurons from rat dorsal root ganglia. FASEB J 15:1037–1043PubMedCrossRefGoogle Scholar
  68. 68.
    Kuslich S, Ulstro C, Michael C (1991) The tissue origin of low back pain and sciatica. Orthop Clin North Am 22:181–187PubMedGoogle Scholar
  69. 69.
    Levin MJ, Cai GY, Manchak MD, Pizer LI (2003) Varicella-zoster virus DNA in cells isolated from human trigeminal ganglia. J Virol 77:6979–6987PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Liem L (2015) Stimulation of the dorsal root ganglion. Prog Neurol Surg 29:213–224PubMedGoogle Scholar
  71. 71.
    Lisney SJW, Devor M (1987) Afterdischarge and interactions among fibers in damaged peripheral nerve in the rat. Brain Res 415:122–136PubMedCrossRefGoogle Scholar
  72. 72.
    Liu C-N, Wall PD, Ben-Dor E, Michaelis M, Amir R, Devor M (2000) Tactile allodynia in the absence of C-fiber activation: altered firing properties of DRG neurons following spinal nerve injury. Pain 85:503–521PubMedCrossRefGoogle Scholar
  73. 73.
    Makin TR, Scholz J, Filippini N, Henderson Slater D, Tracey I, Johansen-Berg H (2013) Phantom pain is associated with preserved structure and function in the former hand area. Nat Commun 4:1570PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Markus A, Lebenthal-Loinger I, Yang IH, Kinchington PR, Goldstein RS (2015) An in vitro model of latency and reactivation of varicella zoster virus in human stem cell-derived neurons. PLoS Pathog 11:e1004885PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Matak I, Bach-Rojecky L, Filipovic B, Lackovic Z (2011) Behavioral and immunohistochemical evidence for central antinociceptive activity of botulinum toxin A. Neuroscience 186:201–207PubMedCrossRefGoogle Scholar
  76. 76.
    Matzner O, Devor M (1987) Contrasting thermal sensitivity of spontaneously active A- and C-fibers in experimental nerve-end neuromas. Pain 30:373–384PubMedCrossRefGoogle Scholar
  77. 77.
    Max MB, Schafer SC, Culnane M, Dubner R, Gracely RH (1988) Association of pain relief with drug side effects in postherpetic neuralgia: a single-dose study of clonidine, codeine, ibuprofen, and placebo. Clin Pharmacol Ther 43:363–371PubMedCrossRefGoogle Scholar
  78. 78.
    Mayer ML, James MH, Russell RJ, Kelly JS, Pasternak CA (1986) Changes in excitability induced by herpes simplex viruses in rat dorsal root ganglion neurons. J Neurosci 6:391–402PubMedCrossRefGoogle Scholar
  79. 79.
    McLachlan E, Janig W, Devor M, Michaelis M (1993) Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature 363:543–546PubMedCrossRefGoogle Scholar
  80. 80.
    Meier T, Wasner G, Faust M, Kuntzer T, Ochsner F, Hueppe M, Bogousslavsky J, Baron R (2003) Efficacy of lidocaine patch 5 % in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 106:151–158PubMedCrossRefGoogle Scholar
  81. 81.
    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
  82. 82.
    Moore RA, Chi CC, Wiffen PJ, Derry S, Rice AS (2015) Oral nonsteroidal anti-inflammatory drugs for neuropathic pain. Cochrane Database Syst Rev 10:CD010902Google Scholar
  83. 83.
    Nitzan-Luques A, Devor M, Tal M (2011) Genotype-selective phenotypic switch in primary afferent neurons contributes to neuropathic pain. Pain 152:2413–2426PubMedCrossRefGoogle Scholar
  84. 84.
    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
  85. 85.
    Nurmikko T, Bowsher D (1990) Somatosensory findings in postherpetic neuralgia. J Neurol Neurosurg Psychiatry 53:135–141PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Nurmikko T, Wells C, Bowsher D (1991) Pain and allodynia in postherpetic neuralgia: role of somatic and sympathetic nervous systems. Acta Neurol Scand 84:146–152PubMedCrossRefGoogle Scholar
  87. 87.
    Oaklander AL, Bowsher D, Galer B, Haanpaa M, Jensen MP (2003) Herpes zoster itch: preliminary epidemiologic data. J Pain 4:338–343PubMedCrossRefGoogle Scholar
  88. 88.
    Onofrio BM, Campa HK (1972) Evaluation of rhizotomy: review of 12 years’ experience. J Neurosurg 36:751–755PubMedCrossRefGoogle Scholar
  89. 89.
    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
  90. 90.
    Park TS, Johnston JM (2006) Surgical techniques of selective dorsal rhizotomy for spastic cerebral palsy. Technical note. Neurosurg Focus 21:e7PubMedGoogle Scholar
  91. 91.
    Patel AJ, Gressot LV, Boatey J, Hwang SW, Brayton A, Jea A (2013) Routine sectioning of the C2 nerve root and ganglion for C1 lateral mass screw placement in children: surgical and functional outcomes. Childs Nerv Syst 29:93–97PubMedCrossRefGoogle Scholar
  92. 92.
    Peppin JF, Albrecht PJ, Argoff C, Gustorff B, Pappagallo M, Rice FL, Wallace MS (2015) Skin matters: a review of topical treatments for chronic pain. Part two: treatments and applications. Pain Ther 4:33–50PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Petersen KL, Rice FL, Farhadi M, Reda H, Rowbotham MC (2010) Natural history of cutaneous innervation following herpes zoster. Pain 150:75–82PubMedCrossRefGoogle Scholar
  94. 94.
    Petersen KL, Rowbotham MC (2007) Relief of post-herpetic neuralgia by surgical removal of painful skin: 5 years later. Pain 131:214–218PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    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 214:219–228PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Prestor B (2001) Microsurgical junctional DREZ coagulation for treatment of deafferentation pain syndromes. Surg Neurol 56:259–265PubMedCrossRefGoogle Scholar
  97. 97.
    Puri N (2011) Modified Jaipur block for the treatment of post-herpetic neuralgia. Int J Dermatol 50:1417–1420PubMedCrossRefGoogle Scholar
  98. 98.
    Radtke C, Vogt PM, Devor M, Kocsis JD (2010) Keratinocytes acting on injured afferents induce extreme neuronal hyperexcitability and chronic pain. Pain 148:94–102PubMedCrossRefGoogle Scholar
  99. 99.
    Reichelt M, Zerboni L, Arvin AM (2008) Mechanisms of varicella-zoster virus neuropathogenesis in human dorsal root ganglia. J Virol 82:3971–3983PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Riopelle JM, Naraghi M, Grush KP (1984) Chronic neuralgia incidence following local anesthetic therapy for herpes zoster. Arch Dermatol 120:747–750PubMedCrossRefGoogle Scholar
  101. 101.
    Rosenak S (1938) Procaine injection treatment of herpes zoster. Lancet:1056–1058CrossRefGoogle Scholar
  102. 102.
    Sawynok J (2014) Topical analgesics for neuropathic pain: preclinical exploration, clinical validation, future development. Eur J Pain 18:465–481PubMedCrossRefGoogle Scholar
  103. 103.
    Sawynok J, Zinger C (2016) Topical amitriptyline and ketamine for post-herpetic neuralgia and other forms of neuropathic pain. Expert Opin Pharmacother 17:601–609CrossRefGoogle Scholar
  104. 104.
    Serra J, Collado A, Sola R, Antonelli F, Torres X, Salgueiro M, Quiles C, Bostock H (2014) Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol 75:196–208PubMedCrossRefGoogle Scholar
  105. 105.
    Shackleton T, Ram S, Black M, Ryder J, Clark GT, Enciso R (2016) The efficacy of botulinum toxin for the treatment of trigeminal and postherpetic neuralgia: a systematic review with meta-analyses. Oral Surg Oral Med Oral Pathol Oral Radiol 122:61–71CrossRefGoogle Scholar
  106. 106.
    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
  107. 107.
    Simone DA, Nolano M, Johnson T, Wendelschafer-Crabb G, Kennedy WR (1998) Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J Neurosci 18:8947–8959PubMedCrossRefGoogle Scholar
  108. 108.
    Sindou M, Mifsud JJ, Boisson D, Goutelle A (1986) Selective posterior rhizotomy in the dorsal root entry zone for treatment of hyperspasticity and pain in the hemiplegic upper limb. Neurosurgery 18:587–595PubMedCrossRefGoogle Scholar
  109. 109.
    Sugar O, Bucy PC (1951) Postherpetic trigeminal neuralgia. AMA Arch Neurol Psychiatry 65:131–145PubMedCrossRefGoogle Scholar
  110. 110.
    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
  111. 111.
    Tandrup T (2004) Unbiased estimates of number and size of rat dorsal root ganglion cells in studies of structure and cell survival. J Neurocytol 33:173–192PubMedCrossRefGoogle Scholar
  112. 112.
    Tandrup T, Woolf CJ, Coggeshall RE (2000) Delayed loss of small dorsal root ganglion cells after transection of the rat sciatic nerve. J Comp Neurol 422:172–180PubMedCrossRefGoogle Scholar
  113. 113.
    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
  114. 114.
    Uceyler N, Valet M, Kafke W, Tolle TR, Sommer C (2014) Local and systemic cytokine expression in patients with postherpetic neuralgia. PLoS One 9:e105269PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Uceyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A, Casanova-Molla J, Reiners K, Sommer C (2013) Small fibre pathology in patients with fibromyalgia syndrome. Brain 136:1857–1867PubMedCrossRefGoogle Scholar
  116. 116.
    van Wijck AJ, Opstelten W, Moons KG, van Essen GA, Stolker RJ, Kalkman CJ, Verheij TJ (2006) The PINE study of epidural steroids and local anaesthetics to prevent postherpetic neuralgia: a randomised controlled trial. Lancet 367:219–224CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    van Wijck AJ, Wallace M, Mekhail N, van Kleef M (2011) Evidence-based interventional pain medicine according to clinical diagnoses. 17. Herpes zoster and post-herpetic neuralgia. Pain Pract 11:88–97PubMedCrossRefGoogle Scholar
  118. 118.
    Vaso A, Adahan HM, Gjika A, Zahaj S, Zhurda T, Vyshka G, Devor M (2014) Peripheral nervous system origin of phantom limb pain. Pain 155:1384–1391PubMedCrossRefGoogle Scholar
  119. 119.
    Wall PD, Devor M (1983) Sensory afferent impulses originate from dorsal root ganglia as well as from the periphery in normal and nerve injured rats. Pain 17:321–339PubMedCrossRefGoogle Scholar
  120. 120.
    Wallace MS, Dyck JB, Rossi SS, Yaksh TL (1996) Computer-controlled lidocaine infusion for the evaluation of neuropathic pain after peripheral nerve injury. Pain 66:69–77PubMedCrossRefGoogle Scholar
  121. 121.
    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
  122. 122.
    Watson CP, Deck JH, Morshead C, Van der Kooy D, Evans RJ (1991) Post-herpetic neuralgia: further post-mortem studies of cases with and without pain. Pain 44:105–117PubMedCrossRefGoogle Scholar
  123. 123.
    Watson CP1, Morshead C, Van der Kooy D, Deck J, Evans RJ (1988) Post-herpetic neuralgia: post-mortem analysis of a case. Pain 34:129–38CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Watson CPN, Midha R, Devor M, Nag S, Munro C, Dostrovsky JO (2000) Trigeminal postherpetic neuralgia postmortem: clinically unilateral, pathologically bilateral. In: Devor M, Rowbotham M, Wiesenfeld-Hallin Z (eds) Proceedings of the 9th world congress on pain, progress in pain research and management, vol 17. IASP Press, Seattle, pp. 733–739Google Scholar
  125. 125.
    White DM, Zimmermann M (1988) Changes in the content and release of substance P and calcitonin-gene related peptide in rat cutaneous nerve neuroma. In: Dubner R, Gebhart G, Bond M (eds) Proceedings of the fifth world congress on pain. Elsevier, Amsterdam, pp. 109–113Google Scholar
  126. 126.
    White J, Sweet W (1969) Pain and the neurosurgeon. Thomas, SpringfieldGoogle Scholar
  127. 127.
    Woolf CJ (1983) Evidence for a central component of postinjury pain hypersensitivity. Nature 306:686–688PubMedCrossRefGoogle Scholar
  128. 128.
    Woolf CJ (2011) Central sensitization: implications for the diagnosis and treatment of pain. Pain 152:S2–15PubMedCrossRefGoogle Scholar
  129. 129.
    Wu CL, Marsh A, Dworkin RH (2000) The role of sympathetic nerve blocks in herpes zoster and postherpetic neuralgia. Pain 87:121–129PubMedCrossRefGoogle Scholar
  130. 130.
    Yang Q, Wu Z, Hadden JK, Odem MA, Zuo Y, Crook RJ, Frost JA, Walters ET (2014) Persistent pain after spinal cord injury is maintained by primary afferent activity. J Neurosci 34:10765–10769PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Yirmiya R, Pollak Y, Morag M, Reichenberg A, Barak O, Avitsur R, Shavit Y, Ovadia H, Weidenfeld J, Morag A, Newman ME, Pollmacher T (2000) Illness, cytokines, and depression. Ann N Y Acad Sci 917:478–487PubMedCrossRefGoogle Scholar
  132. 132.
    Zacks SI, Elliott FA, Langfitt TW (1964) Herpetic neuritis: a light and electron microscopic study. Neurology 14:744–750PubMedCrossRefGoogle Scholar
  133. 133.
    Zerboni L, Arvin A (2015) Neuronal subtype and satellite cell tropism are determinants of varicella-zoster virus virulence in human dorsal root ganglia xenografts in vivo. PLoS Pathog 11:e1004989PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Department of Cell and Developmental BiologyInstitute of Life Sciences and Center for Research on Pain, The Hebrew University of JerusalemJerusalemIsrael

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