Skip to main content

Advertisement

Log in

Sodium channelopathies and pain

  • Ion Channels, Receptors and Transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Chronic pain often represents a severe, debilitating condition. Up to 10% of the worldwide population are affected, and many patients are poorly responsive to current treatment strategies. Nociceptors detect noxious conditions to produce the sensation of pain, and this signal is conveyed to the CNS by means of action potentials. The fast upstroke of action potentials is mediated by voltage-gated sodium channels, of which nine pore-forming α-subunits (Nav1.1–1.9) have been identified. Heterogeneous functional properties and distinct expression patterns denote specialized functions of each subunit. The Nav1.7 and Nav1.8 subunits have emerged as key molecules involved in peripheral pain processing and in the development of an increased pain sensitivity associated with inflammation and tissue injury. Several mutations in the SCN9A gene encoding for Nav1.7 have been identified as important cellular substrates for different heritable pain syndromes. This review aims to cover recent progress on our understanding of how biophysical properties of mutant Nav1.7 translate into an aberrant electrogenesis of nociceptors. We also recapitulate the role of Nav1.8 for peripheral pain processing and of additional sodium channelopathies which have been linked to disorders with pain as a significant component.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Ahmad S, Dahllund L, Eriksson AB, Hellgren D, Karlsson U, Lund P-E, 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 16:2114–2121

    Article  PubMed  CAS  Google Scholar 

  2. Akopian AN, Sivilotti L, Wood JN (1996) A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379:257–262

    Article  PubMed  CAS  Google Scholar 

  3. Akopian AN, Souslova V, England S, Okuse K, Ogata N, Ure J, Smith A, Kerr BJ, McMahon SB, Boyce S, Hill R, Stanfa LC, Dickenson AH, Wood JN (1999) The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci 2:541–548

    Article  PubMed  CAS  Google Scholar 

  4. 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–S29

    Article  PubMed  CAS  Google Scholar 

  5. Attwell D, Cohen I, Eisner D, Ohba M, Ojeda C (1979) The steady state TTX-sensitive (“window”) sodium current in cardiac Purkinje fibres. Pflugers Arch 379:137–142

    Article  PubMed  CAS  Google Scholar 

  6. Beckstein O, Sansom MS (2006) A hydrophobic gate in an ion channel: the closed state of the nicotinic acetylcholine receptor. Phys Biol 3:147–159

    Article  PubMed  CAS  Google Scholar 

  7. Bjornsson A, Gudmundsson G, Gudfinnsson E, Hrafnsdottir M, Benedikz J, Skuladottir S, Kristjansson K, Frigge ML, Kong A, Stefansson K, Gulcher JR (2003) Localization of a gene for migraine without aura to chromosome 4q21. Am J Hum Genet 73:986–993

    Article  PubMed  Google Scholar 

  8. Black JA, Liu S, Tanaka M, Cummins TR, Waxman SG (2004) Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain 108:237–247

    Article  PubMed  CAS  Google Scholar 

  9. Black JA, Nikolajsen L, Kroner K, Jensen TS, Waxman SG (2008) Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann Neurol 64:644–653

    Article  PubMed  Google Scholar 

  10. Blair NT, Bean BP (2002) Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J Neurosci 22:10277–10290

    PubMed  CAS  Google Scholar 

  11. Boucher TJ, Okuse K, Bennett DL, Munson JB, Wood JN, McMahon SB (2000) Potent analgesic effects of GDNF in neuropathic pain states. Science 290:124–127

    Article  PubMed  CAS  Google Scholar 

  12. Castro MJ, Stam AH, Lemos C, de Vries B, Vanmolkot KR, Barros J, Terwindt GM, Frants RR, Sequeiros J, Ferrari MD, Pereira-Monteiro JM, van den Maagdenberg AM (2009) First mutation in the voltage-gated Nav1.1 subunit gene SCN1A with co-occurring familial hemiplegic migraine and epilepsy. Cephalalgia 29:308–313

    Article  PubMed  Google Scholar 

  13. Catterall WA (2000) From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26:13–25

    Article  PubMed  CAS  Google Scholar 

  14. Catterall WA, Goldin AL, Waxman SG (2005) International Union of Pharmacology. XLVII. Nomenclature and Structure-Function Relationships of Voltage-Gated Sodium Channels. Pharmacol Rev 57:397–409

    Article  PubMed  CAS  Google Scholar 

  15. Cestele S, Yarov-Yarovoy V, Qu Y, Sampieri F, Scheuer T, Catterall WA (2006) Structure and function of the voltage sensor of sodium channels probed by a beta-scorpion toxin. J Biol Chem 281:21332–21344

    Article  PubMed  CAS  Google Scholar 

  16. Cestele S, Scalmani P, Rusconi R, Terragni B, Franceschetti S, Mantegazza M (2008) Self-limited hyperexcitability: functional effect of a familial hemiplegic migraine mutation of the Nav1.1 (SCN1A) Na+ channel. J Neurosci 28:7273–7283

    Article  PubMed  CAS  Google Scholar 

  17. Chatelier A, Dahllund L, Eriksson A, Krupp J, Chahine M (2008) Biophysical properties of human Nav1.7 splice variants and their regulation by protein kinase A. J Neurophysiol 99:2241–2250

    Article  PubMed  CAS  Google Scholar 

  18. Cheng X, Dib-Hajj S, Tyrrell L, Waxman S (2008) Mutation I136V alters electrophysiological properties of the NaV1.7 channel in a family with onset of erythromelalgia in the second decade. Mol Pain 4:1

    Article  PubMed  CAS  Google Scholar 

  19. Choi J-S, Zhang L, Dib-Hajj SD, Han C, Tyrrell L, Lin Z, Wang X, Yang Y, Waxman SG (2009) Mexiletine-responsive erythromelalgia due to a new Nav1.7 mutation showing use-dependent current fall-off. Exp Neurol 216:383

    Article  PubMed  CAS  Google Scholar 

  20. Choi JS, Dib-Hajj SD, Waxman SG (2006) Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy. Neurology 67:1563–1567

    Article  PubMed  Google Scholar 

  21. Claes LR, Deprez L, Suls A, Baets J, Smets K, Van Dyck T, Deconinck T, Jordanova A, De Jonghe P (2009) The SCN1A variant database: a novel research and diagnostic tool. Hum Mutat 30:E904–E920

    Article  PubMed  Google Scholar 

  22. Colbert CM, Magee JC, Hoffman DA, Johnston D (1997) Slow recovery from inactivation of Na+ channels underlies the activity-dependent attenuation of dendritic action potentials in hippocampal CA1 pyramidal neurons. J Neurosci 17:6512–6521

    PubMed  CAS  Google Scholar 

  23. Coward K, Plumpton C, Facer P, Birch R, Carlstedt T, Tate S, Bountra C, Anand P (2000) Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states. Pain 85:41–50

    Article  PubMed  CAS  Google Scholar 

  24. 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 444:894–898

    Article  PubMed  CAS  Google Scholar 

  25. Crill WE (1996) Persistent sodium current in mammalian central neurons. Annu Rev Physiol 58:349–362

    Article  PubMed  CAS  Google Scholar 

  26. Cummins TR, Waxman SG (1997) Downregulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury. J Neurosci 17:3503–3514

    PubMed  CAS  Google Scholar 

  27. Cummins TR, Dib-Hajj SD, Waxman SG (2004) Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. J Neurosci 24:8232–8236

    Article  PubMed  CAS  Google Scholar 

  28. Cummins TR, Rush AM (2007) Voltage-gated sodium channel blockers for the treatment of neuropathic pain. Expert Rev Neurother 7:1597–1612

    Article  PubMed  CAS  Google Scholar 

  29. de Vries B, Frants RR, Ferrari MD, van den Maagdenberg AM (2009) Molecular genetics of migraine. Hum Genet 126:115–132

    Article  PubMed  CAS  Google Scholar 

  30. Dib-Hajj S, Black JA, Felts P, Waxman SG (1996) Down-regulation of transcripts for Na channel alpha-SNS in spinal sensory neurons following axotomy. Proc Natl Acad Sci USA 93:14950–14954

    Article  PubMed  CAS  Google Scholar 

  31. 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 128:1847–1854

    Article  PubMed  CAS  Google Scholar 

  32. Dib-Hajj SD, Cummins TR, Black JA, Waxman SG (2007) From genes to pain: Nav1.7 and human pain disorders. Trends Neurosci 30:555–563

    Article  PubMed  CAS  Google Scholar 

  33. Dib-Hajj SD, Estacion M, Jarecki B, Tyrrell L, Fischer T, Lawden M, Cummins TR, Waxman SG (2008) Paroxysmal extreme pain disorder M1627K mutation in human Nav1.7 renders DRG neurons hyperexcitable. Molecular Pain 4:37

    Article  PubMed  CAS  Google Scholar 

  34. Dib-Hajj SD, Yang Y, Waxman SG (2008) Genetics and molecular pathophysiology of Na(v)1.7-related pain syndromes. Adv Genet 63:85–110

    Article  PubMed  CAS  Google Scholar 

  35. Dib-Hajj SD, Binshtok AM, Cummins TR, Jarvis MF, Samad T, Zimmermann K (2009) Voltage-gated sodium channels in pain states: role in pathophysiology and targets for treatment. Brain Res Rev 60:65–83

    Article  PubMed  CAS  Google Scholar 

  36. Dichgans M, Freilinger T, Eckstein G, Babini E, Lorenz-Depiereux B, Biskup S, Ferrari MD, Herzog J, van den Maagdenberg AM, Pusch M, Strom TM (2005) Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366:371–377

    Article  PubMed  CAS  Google Scholar 

  37. Drenth JP, Finley WH, Breedveld GJ, Testers L, Michiels JJ, Guillet G, Taieb A, Kirby RL, Heutink P (2001) The primary erythermalgia-susceptibility gene is located on chromosome 2q31-32. Am J Hum Genet 68:1277–1282

    Article  PubMed  CAS  Google Scholar 

  38. Drenth JP, te Morsche RH, Guillet G, Taieb A, Kirby RL, Jansen JB (2005) SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. J Invest Dermatol 124:1333–1338

    Article  PubMed  CAS  Google Scholar 

  39. Drenth JP, Waxman SG (2007) Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. J Clin Invest 117:3603–3609

    Article  PubMed  CAS  Google Scholar 

  40. Edgerton GB, Blumenthal KM, Hanck DA (2008) Evidence for multiple effects of ProTxII on activation gating in NaV1.5. Toxicon 52:489

    Article  PubMed  CAS  Google Scholar 

  41. Ekberg J, Jayamanne A, Vaughan CW, Aslan S, Thomas L, Mould J, Drinkwater R, Baker MD, Abrahamsen B, Wood JN, Adams DJ, Christie MJ, Lewis RJ (2006) muO-conotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits. Proc Natl Acad Sci USA 103:17030–17035

    Article  PubMed  CAS  Google Scholar 

  42. Escayg A, Heils A, MacDonald BT, Haug K, Sander T, Meisler MH (2001) A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus—and prevalence of variants in patients with epilepsy. Am J Hum Genet 68:866–873

    Article  PubMed  CAS  Google Scholar 

  43. Estacion M, Dib-Hajj SD, Benke PJ, te Morsche RHM, Eastman EM, Macala LJ, Drenth JPH, Waxman SG (2008) NaV1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders. J Neurosci 28:11079–11088

    Article  PubMed  CAS  Google Scholar 

  44. 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 52:767–774

    Article  PubMed  CAS  Google Scholar 

  45. Fertleman CR, Ferrie CD (2006) What’s in a name—familial rectal pain syndrome becomes paroxysmal extreme pain disorder. J Neurol Neurosurg Psychiatry 77:1294–1295

    Article  PubMed  CAS  Google Scholar 

  46. Fertleman CR, Ferrie CD, Aicardi J, Bednarek NA, Eeg-Olofsson O, Elmslie FV, Griesemer DA, Goutieres F, Kirkpatrick M, Malmros IN, Pollitzer M, Rossiter M, Roulet-Perez E, Schubert R, Smith VV, Testard H, Wong V, Stephenson JB (2007) Paroxysmal extreme pain disorder (previously familial rectal pain syndrome). Neurology 69:586–595

    Article  PubMed  CAS  Google Scholar 

  47. Fischer TZ, Gilmore ES, Estacion M, Eastman E, Taylor S, Melanson M, Dib-Hajj SD, Waxman SG (2009) A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia. Ann Neurol 65:733–741

    Article  PubMed  Google Scholar 

  48. Fleidervish IA, Friedman A, Gutnick MJ (1996) Slow inactivation of Na+ current and slow cumulative spike adaptation in mouse and guinea-pig neocortical neurones in slices. J Physiol 493(Pt 1):83–97

    PubMed  CAS  Google Scholar 

  49. Foulkes T, Wood JN (2008) Pain genes. PLoS Genet 4:e1000086

    Article  PubMed  CAS  Google Scholar 

  50. Gargus JJ, Tournay A (2007) Novel mutation confirms seizure locus SCN1A is also familial hemiplegic migraine locus FHM3. Pediatr Neurol 37:407–410

    Article  PubMed  Google Scholar 

  51. Gecz J, Baker E, Donnelly A, Ming JE, McDonald-McGinn DM, Spinner NB, Zackai EH, Sutherland GR, Mulley JC (1999) Fibroblast growth factor homologous factor 2 (FHF2): gene structure, expression and mapping to the Börjeson–Forssman–Lehmann syndrome region in Xq26 delineated by a duplication breakpoint in a BFLS-like patient. Hum Gen 104:56–63

    Article  CAS  Google Scholar 

  52. Gold MS, Reichling DB, Shuster MJ, Levine JD (1996) Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors. Proc Natl Acad Sci USA 93:1108–1112

    Article  PubMed  CAS  Google Scholar 

  53. Gold MS, Levine JD, Correa AM (1998) Modulation of TTX-R INa by PKC and PKA and their role in PGE2-induced sensitization of rat sensory neurons in vitro. J Neurosci 18:10345–10355

    PubMed  CAS  Google Scholar 

  54. Gold MS, Weinreich D, Kim CS, Wang R, Treanor J, Porreca F, Lai J (2003) Redistribution of Na(V)1.8 in uninjured axons enables neuropathic pain. J Neurosci 23:158–166

    PubMed  CAS  Google Scholar 

  55. 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 71:311–319

    Article  PubMed  CAS  Google Scholar 

  56. Goldfarb M (2005) Fibroblast growth factor homologous factors: evolution, structure, and function. Cytokine Growth Factor Rev 16:215–220

    Article  PubMed  CAS  Google Scholar 

  57. Han C, Rush AM, Dib-Hajj SD, Li S, Xu Z, Wang Y, Tyrrell L, Wang X, Yang Y, Waxman SG (2006) Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7. Ann Neurol 59:553–558

    Article  PubMed  CAS  Google Scholar 

  58. Han C, Dib-Hajj SD, Lin Z, Li Y, Eastman EM, Tyrrell L, Cao X, Yang Y, Waxman SG (2009) Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation. Brain 132(Pt 7):1711–1722

    Article  PubMed  Google Scholar 

  59. Harty TP, Dib-Hajj SD, Tyrrell L, Blackman R, Hisama FM, Rose JB, Waxman SG (2006) Na(V)1.7 mutant A863P in erythromelalgia: effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons. J Neurosci 26:12566–12575

    Article  PubMed  CAS  Google Scholar 

  60. Hillsley K, Lin JH, Stanisz A, Grundy D, Aerssens J, Peeters PJ, Moechars D, Coulie B, Stead RH (2006) Dissecting the role of sodium currents in visceral sensory neurons in a model of chronic hyperexcitability using Nav1.8 and Nav1.9 null mice. J Physiol 576:257–267

    Article  PubMed  CAS  Google Scholar 

  61. Iqbal J, Bhat MI, Charoo BA, Syed WA, Sheikh MA, Bhat IN (2009) Experience with oral mexiletine in primary erythromelalgia in children. Ann Saudi Med 29:316–318

    Article  PubMed  Google Scholar 

  62. Jarecki BW, Sheets PL, Jackson IIJO, Cummins TR (2008) Paroxysmal extreme pain disorder mutations within the D3/S4–S5 linker of Nav1.7 cause moderate destabilization of fast-inactivation. J Physiol 586:4137–4153. doi:10.1113/jphysiol.2008.154906

    Article  PubMed  CAS  Google Scholar 

  63. Jarecki BW, Sheets PL, Xiao Y, Jackson JO 2nd, Cummins TR (2009) Alternative splicing of Na(V)1.7 exon 5 increases the impact of the painful PEPD mutant channel I1461T. Channels (Austin) 3:259–267

    Google Scholar 

  64. 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 C, Mikusa JP, Hernandez G, Gauvin D, Wade C, Zhu C, Pai M, Scanio M, Shi L, Drizin I, Gregg R, Matulenko M, Hakeem A, Gross 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 104:8520–8525

    Article  PubMed  CAS  Google Scholar 

  65. John VH, Main MJ, Powell AJ, Gladwell ZM, Hick C, Sidhu HS, Clare JJ, Tate S, Trezise DJ (2004) Heterologous expression and functional analysis of rat Nav1.8 (SNS) voltage-gated sodium channels in the dorsal root ganglion neuroblastoma cell line ND7-23. Neuropharmacology 46:425–438

    Article  PubMed  CAS  Google Scholar 

  66. Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413:203–210

    Article  PubMed  CAS  Google Scholar 

  67. Jung HY, Mickus T, Spruston N (1997) Prolonged sodium channel inactivation contributes to dendritic action potential attenuation in hippocampal pyramidal neurons. J Neurosci 17:6639–6646

    PubMed  CAS  Google Scholar 

  68. Kahlig KM, Rhodes TH, Pusch M, Freilinger T, Pereira-Monteiro JM, Ferrari MD, van den Maagdenberg AM, Dichgans M, George AL Jr (2008) Divergent sodium channel defects in familial hemiplegic migraine. Proc Natl Acad Sci USA 105:9799–9804

    Article  PubMed  Google Scholar 

  69. Kerr BJ, Souslova V, McMahon SB, Wood JN (2001) A role for the TTX-resistant sodium channel Nav 1.8 in NGF-induced hyperalgesia, but not neuropathic pain. NeuroReport 12:3077–3080

    Article  PubMed  CAS  Google Scholar 

  70. Kiernan MC, Krishnan AV, Lin CS, Burke D, Berkovic SF (2005) Mutation in the Na+ channel subunit SCN1B produces paradoxical changes in peripheral nerve excitability. Brain 128:1841–1846

    Article  PubMed  Google Scholar 

  71. Koltzenburg M, Scadding J (2001) Neuropathic pain. Curr Opin Neurol 14:641–647

    Article  PubMed  CAS  Google Scholar 

  72. Kort ME, Drizin I, Gregg RJ, Scanio MJ, Shi L, Gross MF, Atkinson RN, Johnson MS, Pacofsky GJ, Thomas JB, Carroll WA, Krambis MJ, Liu D, Shieh CC, Zhang X, Hernandez G, Mikusa JP, Zhong C, Joshi S, Honore P, Roeloffs R, Marsh KC, Murray BP, Liu J, Werness S, Faltynek CR, Krafte DS, Jarvis MF, Chapman ML, Marron BE (2008) Discovery and biological evaluation of 5-aryl-2-furfuramides, potent and selective blockers of the Nav1.8 sodium channel with efficacy in models of neuropathic and inflammatory pain. J Med Chem 51:407–416

    Article  PubMed  CAS  Google Scholar 

  73. Kuhnert SM, Phillips WJ, Davis MD (1999) Lidocaine and mexiletine therapy for erythromelalgia. Arch Dermatol 135:1447–1449

    Article  PubMed  CAS  Google Scholar 

  74. Kuo A, Gulbis JM, Antcliff JF, Rahman T, Lowe ED, Zimmer J, Cuthbertson J, Ashcroft FM, Ezaki T, Doyle DA (2003) Crystal structure of the potassium channel KirBac1.1 in the closed state. Science 300:1922–1926

    Article  PubMed  CAS  Google Scholar 

  75. Lai J, Gold MS, Kim CS, Bian D, Ossipov MH, Hunter JC, Porreca F (2002) Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 95:143–152

    Article  PubMed  CAS  Google Scholar 

  76. Lai J, Hunter JC, Porreca F (2003) The role of voltage-gated sodium channels in neuropathic pain. Curr Opin Neurobiol 13:291–297

    Article  PubMed  CAS  Google Scholar 

  77. Laird JM, Souslova V, Wood JN, Cervero F (2002) Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice. J Neurosci 22:8352–8356

    PubMed  CAS  Google Scholar 

  78. Lampert A, Dib-Hajj S, Tyrrell L, Waxman S (2006) Size matters: erythromelalgia mutation S241T in Nav1.7 alters channel gating. J Biol Chem 281:36029–36035

    Article  PubMed  CAS  Google Scholar 

  79. Lampert A, O’Reilly AO, Dib-Hajj SD, Tyrrell L, Wallace BA, Waxman SG (2008) A pore-blocking hydrophobic motif at the cytoplasmic aperture of the closed-state Nav1.7 channel is disrupted by the erythromelalgia-associated F1449V mutation. J Biol Chem 283:24118–24127

    Article  PubMed  CAS  Google Scholar 

  80. Lampert A, Dib-Hajj SD, Eastman EM, Tyrrell L, Lin Z, Yang Y, Waxman SG (2009) Erythromelalgia mutation L823R shifts activation and inactivation of threshold sodium channel Nav1.7 to hyperpolarized potentials. Biochem Biophys Res Commun 390:319–324

    Article  PubMed  CAS  Google Scholar 

  81. Lee MJ, Yu HS, Hsieh ST, Stephenson DA, Lu CJ, Yang CC (2007) Characterization of a familial case with primary erythromelalgia from Taiwan. J Neurol 254:210–214

    Article  PubMed  Google Scholar 

  82. Leffler A, Reiprich A, Mohapatra DP, Nau C (2007) Use-dependent block by lidocaine but not amitriptyline is more pronounced in tetrodotoxin (TTX)-resistant Nav1.8 than in TTX-sensitive Na+ channels. J Pharmacol Exp Ther 320:354–364

    Article  PubMed  CAS  Google Scholar 

  83. Long SB, Campbell EB, Mackinnon R (2005) Voltage sensor of Kv1.2: structural basis of electromechanical coupling. Science 309:903–908

    Article  PubMed  CAS  Google Scholar 

  84. Meisler MH, Kearney J, Ottman R, Escayg A (2001) Identification of epilepsy genes in human and mouse. Annu Rev Genet 35:567–588

    Article  PubMed  CAS  Google Scholar 

  85. Michiels JJ, te Morsche RH, Jansen JB, Drenth JP (2005) Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Nav1.7. Arch Neurol 62:1587–1590

    Article  PubMed  Google Scholar 

  86. Mickus T, Jung H, Spruston N (1999) Properties of slow, cumulative sodium channel inactivation in rat hippocampal CA1 pyramidal neurons. Biophys J 76:846–860

    Article  PubMed  CAS  Google Scholar 

  87. Middleton RE, Warren VA, Kraus RL, Hwang JC, Liu CJ, Dai G, Brochu RM, Kohler MG, Gao Y-D, Garsky VM, Bogusky MJ, Mehl JT, Cohen CJ, Smith MM (2002) Two tarantula peptides inhibit activation of multiple sodium channels. Biochemistry 41:14734–14747

    Article  PubMed  CAS  Google Scholar 

  88. Miyazawa A, Fujiyoshi Y, Unwin N (2003) Structure and gating mechanism of the acetylcholine receptor pore. Nature 423:949–955

    Article  PubMed  CAS  Google Scholar 

  89. Nassar MA, Stirling LC, Forlani G, Baker MD, Matthews EA, Dickenson AH, Wood JN (2004) Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc Natl Acad Sci USA 101:12706–12711

    Article  PubMed  CAS  Google Scholar 

  90. Nathan A, Rose JB, Guite JW, Hehir D, Milovcich K (2005) Primary erythromelalgia in a child responding to intravenous lidocaine and oral mexiletine treatment. Pediatrics 115:e504–e507

    Article  PubMed  Google Scholar 

  91. Natkunarajah J, Atherton D, Elmslie F, Mansour S, Mortimer P (2009) Treatment with carbamazepine and gabapentin of a patient with primary erythermalgia (erythromelalgia) identified to have a mutation in the SCN9A gene, encoding a voltage-gated sodium channel. Clin Exp Dermatol 34:e640–e642

    Article  PubMed  CAS  Google Scholar 

  92. Nilsen KB, Nicholas AK, Woods CG, Mellgren SI, Nebuchennykh M, Aasly J (2009) Two novel SCN9A mutations causing insensitivity to pain. Pain 143:155–158

    Article  PubMed  CAS  Google Scholar 

  93. O’Reilly AO, Khambay BP, Williamson MS, Field LM, Wallace BA, Davies TG (2006) Modelling insecticide-binding sites in the voltage-gated sodium channel. Biochem J 396:255–263

    Article  PubMed  Google Scholar 

  94. Ong BH, Tomaselli GF, Balser JR (2000) A structural rearrangement in the sodium channel pore linked to slow inactivation and use dependence. J Gen Physiol 116:653–662

    Article  PubMed  CAS  Google Scholar 

  95. Priest BT, Blumenthal KM, Smith JJ, Warren VA, Smith MM (2007) ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels. Toxicon 49:194

    Article  PubMed  CAS  Google Scholar 

  96. Raymond CK, Castle J, Garrett-Engele P, Armour CD, Kan Z, Tsinoremas N, Johnson JM (2004) Expression of alternatively spliced sodium channel alpha-subnit genes: unique splicing patterns are observed in dorsal root ganglia. J Biol Chem 279:46234–46241. doi:10.1074/jbc.M406387200

    Article  PubMed  CAS  Google Scholar 

  97. Renganathan M, Cummins TR, Waxman SG (2001) Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons. J Neurophysiol 86:629–640

    PubMed  CAS  Google Scholar 

  98. Roza C, Laird JM, Souslova V, Wood JN, Cervero F (2003) The tetrodotoxin-resistant Na+ channel Nav1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J Physiol 550:921–926

    Article  PubMed  CAS  Google Scholar 

  99. Rush AM, Elliott JR (1997) Phenytoin and carbamazepine: differential inhibition of sodium currents in small cells from adult rat dorsal root ganglia. Neurosci Lett 226:95–98

    Article  PubMed  CAS  Google Scholar 

  100. Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG (2006) A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci USA 103:8245–8250

    Article  PubMed  CAS  Google Scholar 

  101. Rush AM, Cummins TR, Waxman SG (2007) Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. J Physiol 579:1–14

    Article  PubMed  CAS  Google Scholar 

  102. Sangameswaran L, Delgado SG, Fish LM, Koch BD, Jakeman LB, Stewart GR, Sze P, Hunter JC, Eglen RM, Herman RC (1996) Structure and function of a novel voltage-gated, tetrodotoxin-resistant sodium channel specific to sensory neurons. J Biol Chem 271:5953–5956

    Article  PubMed  CAS  Google Scholar 

  103. Scheib H, McLay I, Guex N, Clare JJ, Blaney FE, Dale TJ, Tate SN, Robertson GM (2006) Modeling the pore structure of voltage-gated sodium channels in closed, open, and fast-inactivated conformation reveals details of site 1 toxin and local anesthetic binding. J Mol Model 12:813–822

    Article  PubMed  CAS  Google Scholar 

  104. Schmalhofer W, Calhoun J, Burrows R, Bailey T, Kohler MG, Weinglass AB, Kaczorowski GJ, Garcia ML, Koltzenburg M, Priest BT (2008) ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Mol Pharmacol 74:1476–1484. doi:10.1124/mol.108.047670

    Article  PubMed  CAS  Google Scholar 

  105. Scholz J, Woolf CJ (2002) Can we conquer pain? Nat Neurosci 5(Suppl):1062–1067

    Article  PubMed  CAS  Google Scholar 

  106. Sheets PL, Jackson JO 2nd, Waxman SG, Dib-Hajj SD, Cummins TR (2007) A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity. J Physiol 581:1019–1031

    Article  PubMed  CAS  Google Scholar 

  107. Sheets PL, Heers C, Stoehr T, Cummins TR (2008) Differential block of sensory neuronal voltage-gated sodium channels by lacosamide [(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide], lidocaine, and carbamazepine. J Pharmacol Exp Ther 326:89–99

    Article  PubMed  CAS  Google Scholar 

  108. Singh NA, Pappas C, Dahle EJ, Claes LRF, Pruess TH, De Jonghe P, Thompson J, Dixon M, Gurnett C, Peiffer A, White HS, Filloux F, Leppert MF (2009) A role of SCN9A in human epilepsies. As a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genet 5:e1000649

    Article  PubMed  CAS  Google Scholar 

  109. Smith JJ, Cummins TR, Alphy S, Blumenthal KM (2007) Molecular interactions of the gating modifier toxin ProTx-II with Nav1.5: implied existence of a novel toxin binding site coupled to activation. J Biol Chem 282:12687–12697

    Article  PubMed  CAS  Google Scholar 

  110. Song JH, Nagata K, Huang CS, Yeh JZ, Narahashi T (1996) Differential block of two types of sodium channels by anticonvulsants. NeuroReport 7:3031–3036

    Article  PubMed  CAS  Google Scholar 

  111. Takahashi K, Saitoh M, Hoshino H, Mimaki M, Yokoyama Y, Takamizawa M, Mizuguchi M, Lin ZM, Yang Y, Igarashi T (2007) A case of primary erythermalgia. Wintry hypothermia and encephalopathy. Neuropediatrics 38:157

    Article  PubMed  CAS  Google Scholar 

  112. Tanaka M, Cummins TR, Ishikawa K, Dib-Hajj SD, Black JA, Waxman SG (1998) SNS Na+ channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model. NeuroReport 9:967–972

    Article  PubMed  CAS  Google Scholar 

  113. Toib A, Lyakhov V, Marom S (1998) Interaction between duration of activity and time course of recovery from slow inactivation in mammalian brain Na+ channels. J Neurosci 18:1893–1903

    PubMed  CAS  Google Scholar 

  114. Unwin N (1995) Acetylcholine receptor channel imaged in the open state. Nature 373:37–43

    Article  PubMed  CAS  Google Scholar 

  115. Vahedi K, Depienne C, Le Fort D, Riant F, Chaine P, Trouillard O, Gaudric A, Morris MA, Leguern E, Tournier-Lasserve E, Bousser MG (2009) Elicited repetitive daily blindness: a new phenotype associated with hemiplegic migraine and SCN1A mutations. Neurology 72:1178–1183

    Article  PubMed  CAS  Google Scholar 

  116. Vanmolkot KR, Babini E, de Vries B, Stam AH, Freilinger T, Terwindt GM, Norris L, Haan J, Frants RR, Ramadan NM, Ferrari MD, Pusch M, van den Maagdenberg AM, Dichgans M (2007) The novel p.L1649Q mutation in the SCN1A epilepsy gene is associated with familial hemiplegic migraine: genetic and functional studies. Mutation in brief #957. Online. Hum Mutat 28:522

    Article  PubMed  Google Scholar 

  117. Wang CG, Gilles N, Hamon A, Le Gall F, Stankiewicz M, Pelhate M, Xiong YM, Wang DC, Chi CW (2003) Exploration of the functional site of a scorpion alpha-like toxin by site-directed mutagenesis. Biochemistry 42:4699–4708

    Article  PubMed  CAS  Google Scholar 

  118. Wang S-Y, Wang GK (2003) Voltage-gated sodium channels as primary targets of diverse lipid-soluble neurotoxins. Cell Signal 15:151

    Article  PubMed  CAS  Google Scholar 

  119. Woolf CJ, Ma Q (2007) Nociceptors—noxious stimulus detectors. Neuron 55:353–364

    Article  PubMed  CAS  Google Scholar 

  120. Xiao Y, Bingham J-P, Zhu W, Moczydlowski E, Liang S, Cummins TR (2008) Tarantula huwentoxin-IV inhibits neuronal sodium channels by binding to receptor site 4 and trapping the domain II voltage sensor in the closed configuration. J Biol Chem 283:27300–27313

    Article  PubMed  CAS  Google Scholar 

  121. Yang Y, Wang Y, Li S, Xu Z, Li H, Ma L, Fan J, Bu D, Liu B, Fan Z, Wu G, Jin J, Ding B, Zhu X, Shen Y (2004) Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet 41:171–174

    Article  PubMed  CAS  Google Scholar 

  122. Zimmermann K, Leffler A, Babes A, Cendan CM, Carr RW, Kobayashi J, Nau C, Wood JN, Reeh PW (2007) Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature 447:855–858

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

We thank Julian Knott for design advice. ALa was supported by grants from the Deutsche Forschungsgemeinschaft LA2740/2-1 and Robert-Bosch-Foundation: Fast Track Program. AOR was supported in part by a grant from the UK Biotechnology and Biological Science Research Council to B.A. Wallace. PR was supported by a grant from the Deutsche Forschungsgemeinschaft KFO 130 and ALe from the Deutsche Forschungsgemeinschaft NA350/3-2 and KFO 130.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Angelika Lampert.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lampert, A., O’Reilly, A.O., Reeh, P. et al. Sodium channelopathies and pain. Pflugers Arch - Eur J Physiol 460, 249–263 (2010). https://doi.org/10.1007/s00424-009-0779-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-009-0779-3

Keywords

Navigation