medgenМедицинская генетикаMedical Genetics2073-7998Publishing House «Genius Media» LLCmedgen-223Research ArticleНАУЧНЫЕ ОБЗОРЫREVIEWРоль мутаций потенциалзависимых натриевых каналов в патогенезе нейропатической болиThe roles of voltage-gated sodium channels mutations in mechanisms of neuropathic painПетроваМ. М.PetrovaM. M.noemail@neicon.ruПронинаЕ. А.ProninaE. A.noemail@neicon.ruШнайдерН. А.ShnayderN. A.noemail@neicon.ruДмитренкоД. В.DmytrenkoD. V.noemail@neicon.ruСтрогановаМ. В.StroganovaM. V.noemail@neicon.ruБоброваО. П.BobrovaO. P.noemail@neicon.ruКрасноярский государственный медицинский университет им. проф. В.Ф. Войно-ЯсенецкогоРоссияKrasnoyarsk State Medical UniversityRussian Federation201718042017161310Copyright © Петрова М.М., Пронина Е.А., Шнайдер Н.А., Дмитренко Д.В., Строганова М.В., Боброва О.П., 20172017Петрова М.М., Пронина Е.А., Шнайдер Н.А., Дмитренко Д.В., Строганова М.В., Боброва О.П.Petrova M.M., Pronina E.A., Shnayder N.A., Dmytrenko D.V., Stroganova M.V., Bobrova O.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.medgen-journal.ru/jour/article/view/223

Многие подтипы натриевых каналов локализуются в клетках периферической нервной системы и играют важную роль в формировании потенциала действия и возбудимости периферической нервной системы. Набор этих каналов важен для получения ощущения любого типа боли. Четыре изоформы натриевых каналов Na+ 1.3, 1.7, 1.8 и 1.9 могут быть вовлечены в патогенез нейропатической боли. Последние генетические исследования человека и трансгенных животных показывают, что натриевые каналы связаны с различными типами боли и могут являться мишенями для терапевтического воздействия, в том числе при нейропатической боли.

Voltage-gated sodium channels are critical for the generation and conduction of nerve impulses. These channels are responsible for transmitting noxious information to the central nervous system. Individual isoforms of voltage-gated sodium channels have been linked to particular type of pain. Four isoforms of Na+ channels, Na+ 1.3, 1.7, 1.8, and 1.9, have been implicated in the pathogenesis of neuropathic pain. New genetic data from both human studies and transgenic mouse models suggest that specific voltage-gated sodium channel subtypes are associated with specific types of pain and, as consequence, may be useful analgetic drug targets for a variety of pain types including neuropathic pain.

потенциалзависимые натриевые каналымутациинейропатическая больvoltage-gated sodium channelsmutationneuropathic painReferencesДимитриев ДА, Сапёрова ЕВ. Электрофизиология кардиомиоцита: учеб. Пособие. Чебоксары:Чуваш. гос. пед. ун-т; 2009. 102 с.Димитриев ДА, Сапёрова ЕВ. Электрофизиология кардиомиоцита: учеб. Пособие. Чебоксары:Чуваш. гос. пед. ун-т; 2009. 102 с.Салмина АБ, Шнайдер НА, Михуткина СВ Современные представления об ионных каналах и каналопатиях (обзор литературы). Сибирское медицинское обозрение. 2005;(1):75-78.Салмина АБ, Шнайдер НА, Михуткина СВ Современные представления об ионных каналах и каналопатиях (обзор литературы). Сибирское медицинское обозрение. 2005;(1):75-78.Benarroch EE. Sodium channels and pain. Neurology 2007;68(3):233-6. 10.1212/01.wnl.0000252951.48745.a1Benarroch EE. Sodium channels and pain. Neurology 2007;68(3):233-6. 10.1212/01.wnl.0000252951.48745.a1Devor M Sodium channels and mechanisms of neuropathic pain. J Pain. 2006; 7:S3-S12. DOI:10.1016/j.jpain.2005.09.006Devor M Sodium channels and mechanisms of neuropathic pain. J Pain. 2006; 7:S3-S12. DOI:10.1016/j.jpain.2005.09.006Liu M, Wood JN The roles of sodium channels in nociception: implications for mechanisms of neuropathic pain. Pain Med. 2011 Jul;12 Suppl 3:S93-9. doi: 10.1111/j.1526-4637.2011.01158.xLiu M, Wood JN The roles of sodium channels in nociception: implications for mechanisms of neuropathic pain. Pain Med. 2011 Jul;12 Suppl 3:S93-9. doi: 10.1111/j.1526-4637.2011.01158.xMisawa S Pathophysiology of neuropathic pain: Na+ channel and hyperexcitability of primary afferents Brain Nerve. 2012 Nov;64(11):1249-53. PMID:23131735Misawa S Pathophysiology of neuropathic pain: Na+ channel and hyperexcitability of primary afferents Brain Nerve. 2012 Nov;64(11):1249-53. PMID:23131735Shou WT, Zhang SH, Chen Z Role of voltage-sodium channels in neuropathic pain. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2011 Mar;40(2):217-21. PMID:21488221Shou WT, Zhang SH, Chen Z Role of voltage-sodium channels in neuropathic pain. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2011 Mar;40(2):217-21. PMID:21488221Бокерия ОЛ, Ахобеков АА Ионные каналы и их роль в развитии нарушений ритма сердца. Анналы аритмологии. 2014;(3):176-184. Bockeria OL, Akhobekov AA. Ion channels and their role in the development of arrhythmias. Annaly aritmologii. 2014; 11(3): 176-184. doi:10.15275/annaritmol.2014.3.6Бокерия ОЛ, Ахобеков АА Ионные каналы и их роль в развитии нарушений ритма сердца. Анналы аритмологии. 2014;(3):176-184. Bockeria OL, Akhobekov AA. Ion channels and their role in the development of arrhythmias. Annaly aritmologii. 2014; 11(3): 176-184. doi:10.15275/annaritmol.2014.3.6Дмитренко ДВ, Шнайдер НА, Мартынова ГП и др. Мутации натриевых каналов как генетический предиктор фебрильных приступов у детей Современные проблемы науки и образования. 2015;(5). Dmitrenko DV, Shnayder NA, Martynova G.P. et al. Sodium channel mutations as genetics predictors of febrile seizures in children. Problems of Modern Science and Education. 2015;(5). http://www.science-education.ru/ru/article/view?id=22774Дмитренко ДВ, Шнайдер НА, Мартынова ГП и др. Мутации натриевых каналов как генетический предиктор фебрильных приступов у детей Современные проблемы науки и образования. 2015;(5). Dmitrenko DV, Shnayder NA, Martynova G.P. et al. Sodium channel mutations as genetics predictors of febrile seizures in children. Problems of Modern Science and Education. 2015;(5). http://www.science-education.ru/ru/article/view?id=22774Wood JN, Boorman JP, Okuse K, Baker MD. Voltage-gated sodium channels and pain pathways. J Neurobiol 2004;61(1):55-71. doi:10.1002/neu.20094Wood JN, Boorman JP, Okuse K, Baker MD. Voltage-gated sodium channels and pain pathways. J Neurobiol 2004;61(1):55-71. doi:10.1002/neu.20094Minett MS, Nassar MA, Clark AK, et al. Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons Nat Commun. 2012 April 24; 3:791. DOI:10.1038/ncomms1795Minett MS, Nassar MA, Clark AK, et al. Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons Nat Commun. 2012 April 24; 3:791. DOI:10.1038/ncomms1795Black JA, Liu S, Tanaka M, et al. Changes in the expression of tetrodotoxinsensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain. 2004; 108:237-247. doi:10.1016/j.pain.2003.12.035Black JA, Liu S, Tanaka M, et al. Changes in the expression of tetrodotoxinsensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain. 2004; 108:237-247. doi:10.1016/j.pain.2003.12.035Nassar MA, Stirling LC, Forlani G, et al. Nociceptorspecific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc Natl Acad Sci U S A. 2004; 101:12706-12711. doi: 10.1073/pnas.0404915101Nassar MA, Stirling LC, Forlani G, et al. Nociceptorspecific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc Natl Acad Sci U S A. 2004; 101:12706-12711. doi: 10.1073/pnas.0404915101Chattopadhyay M, Mata M, Fink DJ. Vector-mediated release of GABA attenuates pain-related behaviors and reduces Na(V)1.7 in DRG neurons. Eur J Pain. 2011 Oct;15(9):913-20. doi:10.1016/j.ejpain.2011.03.007Chattopadhyay M, Mata M, Fink DJ. Vector-mediated release of GABA attenuates pain-related behaviors and reduces Na(V)1.7 in DRG neurons. Eur J Pain. 2011 Oct;15(9):913-20. doi:10.1016/j.ejpain.2011.03.007Chattopadhyay M, Mata M, Fink DJ Continuous delta opioid receptor activation reduces neuronal voltage gated sodium channel (NaV1.7) levels through activation of protein kinase C in painful diabetic neuropathy J Neurosci. 2008 June 25;28(26):6652-6658. doi: 10.1523/JNEUROSCI.5530-07.2008Chattopadhyay M, Mata M, Fink DJ Continuous delta opioid receptor activation reduces neuronal voltage gated sodium channel (NaV1.7) levels through activation of protein kinase C in painful diabetic neuropathy J Neurosci. 2008 June 25;28(26):6652-6658. doi: 10.1523/JNEUROSCI.5530-07.2008Hong S, Morrow TJ, Paulson PE, et al. Early painful diabetic neuropathy is associated with differential changes in tetrodotoxin-sensitive and -resistant sodium channels in dorsal root ganglion neurons in the rat. J Biol Chem. 2004;279:29341-29350. doi: 10.1074/jbc.M404167200Hong S, Morrow TJ, Paulson PE, et al. Early painful diabetic neuropathy is associated with differential changes in tetrodotoxin-sensitive and -resistant sodium channels in dorsal root ganglion neurons in the rat. J Biol Chem. 2004;279:29341-29350. doi: 10.1074/jbc.M404167200Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 14;444(7121):894-8. doi: 10.1038/nature05413Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 14;444(7121):894-8. doi: 10.1038/nature05413Choi JS, Dib-Hajj SD, Waxman SG. Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy. Neurology. 2006; 67:1563-1567. doi:10.1212/01.wnl.0000231514.33603.1eChoi JS, Dib-Hajj SD, Waxman SG. Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy. Neurology. 2006; 67:1563-1567. doi:10.1212/01.wnl.0000231514.33603.1eDib-Hajj SD, Rush AM, Cummins TR, et al. Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Brain. 2005;128:1847-1854. doi:10.1093/brain/awh514Dib-Hajj SD, Rush AM, Cummins TR, et al. Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Brain. 2005;128:1847-1854. doi:10.1093/brain/awh514Yang Y, Wang Y, Li S, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet. 2004; 41:171-174. PMCID:PMC1735695Yang Y, Wang Y, Li S, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet. 2004; 41:171-174. PMCID:PMC1735695Dib-Hajj SD, Yang Y, Waxman SG Genetics and molecular pathophysiology of Na(v)1.7-related pain syndromes. Adv Genet. 2008;63:85-110. doi: 10.1016/S0065-2660(08)01004-3Dib-Hajj SD, Yang Y, Waxman SG Genetics and molecular pathophysiology of Na(v)1.7-related pain syndromes. Adv Genet. 2008;63:85-110. doi: 10.1016/S0065-2660(08)01004-3Fertleman CR, Baker MD, Parker KA, et al.SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron. 2006; 52:767-774 doi:10.1016/j.neuron.2006.10.006Fertleman CR, Baker MD, Parker KA, et al.SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron. 2006; 52:767-774 doi:10.1016/j.neuron.2006.10.006Dib-Hajj SD, Black JA, Waxman SC. Voltage-gated sodium cannels: therapeutic targets for pain. Pain Med. 2009;10:1260-1269. doi: 10.1111/j.1526-4637.2009.00719.xDib-Hajj SD, Black JA, Waxman SC. Voltage-gated sodium cannels: therapeutic targets for pain. Pain Med. 2009;10:1260-1269. doi: 10.1111/j.1526-4637.2009.00719.xOrstavik K., Jorum E. Microneurographic findings of relevance to pain in patients with erythromelalgia and patients with diabetic neuropathy. Neurosci Lett. 2010;470:108-114. doi:10.1016/j.neulet.2009.05.061Orstavik K., Jorum E. Microneurographic findings of relevance to pain in patients with erythromelalgia and patients with diabetic neuropathy. Neurosci Lett. 2010;470:108-114. doi:10.1016/j.neulet.2009.05.061Orstavik K., Weidner C., Schmidt R. et al. Pathological C-fibres in patients with a chronic painful condition. Brain. 2003;126:567-578. PMID:12566278Orstavik K., Weidner C., Schmidt R. et al. Pathological C-fibres in patients with a chronic painful condition. Brain. 2003;126:567-578. PMID:12566278Слободин ТН. Патогенез и современные подходы к лечению хронической боли Украiнський вiсник психоневрологii. 2012;20(73):106-113.Слободин ТН. Патогенез и современные подходы к лечению хронической боли Украiнський вiсник психоневрологii. 2012;20(73):106-113.Tang Z, Chen Z, Tang B, Jiang H Primary erythromelalgia: a review. Orphanet J Rare Dis. 2015 Sep 30;10:127. doi: 10.1186/s13023-015-0347-1. doi:10.1186/s13023-015-0347-1Tang Z, Chen Z, Tang B, Jiang H Primary erythromelalgia: a review. Orphanet J Rare Dis. 2015 Sep 30;10:127. doi: 10.1186/s13023-015-0347-1. doi:10.1186/s13023-015-0347-1Faber CG, Hoeijmakers JG, Ahn HS et al. Gain of function Na(V)1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2012; 71: 26-39. doi: 10.1002/ana.22485Faber CG, Hoeijmakers JG, Ahn HS et al. Gain of function Na(V)1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2012; 71: 26-39. doi: 10.1002/ana.22485Hoeijmakers JG, Merkies IS, Gerrits MM, et al. Genetic aspects of sodium channelopathy in small fiber neuropathy. Clin Genet. 2012 Oct;82(4):351-8. doi: 10.1111/j.1399-0004.2012.01937.xHoeijmakers JG, Merkies IS, Gerrits MM, et al. Genetic aspects of sodium channelopathy in small fiber neuropathy. Clin Genet. 2012 Oct;82(4):351-8. doi: 10.1111/j.1399-0004.2012.01937.xReimann F, Cox JJ, Belfer I et al. Pain perception is altered by a nucleotide polymorphism in SCN9A. Proc Natl Acad Sci U S A 2010; 107: 5148-5153. doi:10.1073/pnas.0913181107Reimann F, Cox JJ, Belfer I et al. Pain perception is altered by a nucleotide polymorphism in SCN9A. Proc Natl Acad Sci U S A 2010; 107: 5148-5153. doi:10.1073/pnas.0913181107Valdes AM, Arden NK, Vaughn FL et al. Role of the Nav1.7 R1150Wamino acid change in susceptibility to symptomatic knee osteoarthritis and multiple regional pain. Arthritis Care Res (Hoboken) 2011; 63: 440-444. doi:10.1002/acr.20375Valdes AM, Arden NK, Vaughn FL et al. Role of the Nav1.7 R1150Wamino acid change in susceptibility to symptomatic knee osteoarthritis and multiple regional pain. Arthritis Care Res (Hoboken) 2011; 63: 440-444. doi:10.1002/acr.20375Holliday KL, Thomson W, Neogi T, et al. The non-synonymous SNP, R1150W, in SCN9A is not associated with chronic widespread pain susceptibility. Mol Pain. 2012 Sep 24;8:72. doi: 10.1186/1744-8069-8-72.Holliday KL, Thomson W, Neogi T, et al. The non-synonymous SNP, R1150W, in SCN9A is not associated with chronic widespread pain susceptibility. Mol Pain. 2012 Sep 24;8:72. doi: 10.1186/1744-8069-8-72.Vargas-Alarcon G, Alvarez-Leon E, Fragoso JM, et al. A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia. BMC Musculoskelet Disord. 2012 Feb 20;13:23. doi: 10.1186/1471-2474-13-23.Vargas-Alarcon G, Alvarez-Leon E, Fragoso JM, et al. A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia. BMC Musculoskelet Disord. 2012 Feb 20;13:23. doi: 10.1186/1471-2474-13-23.Li QS, Cheng P, Favis R, et al. SCN9A Variants May Implicated in Neuropathic Pain Associated With Diabetic Peripheral Neuropathy andPain Severity. Clin J Pain. 2015 Nov;31(11):976-82. doi: 10.1097/AJP.0000000000000205.Li QS, Cheng P, Favis R, et al. SCN9A Variants May Implicated in Neuropathic Pain Associated With Diabetic Peripheral Neuropathy andPain Severity. Clin J Pain. 2015 Nov;31(11):976-82. doi: 10.1097/AJP.0000000000000205.Duan G, Guo S, Zhang Y et al. The Effect of SCN9A Variation on Basal Pain Sensitivity in the General Population: An Experimental Study in Young Women. J Pain. 2015 Oct;16(10):971-80. doi: 10.1016/j.jpain.2015.06.011.Duan G, Guo S, Zhang Y et al. The Effect of SCN9A Variation on Basal Pain Sensitivity in the General Population: An Experimental Study in Young Women. J Pain. 2015 Oct;16(10):971-80. doi: 10.1016/j.jpain.2015.06.011.Zhang Q, Chibalina MV, Bengtsson M, et al. Na+ current properties in islet a- and b-cells reflect cell-specific Scn3a and Scn9a expression J Physiol. 2014 November 1;592(Pt 21): 4677-4696. doi:10.1113/jphysiol.2014.274209Zhang Q, Chibalina MV, Bengtsson M, et al. Na+ current properties in islet a- and b-cells reflect cell-specific Scn3a and Scn9a expression J Physiol. 2014 November 1;592(Pt 21): 4677-4696. doi:10.1113/jphysiol.2014.274209Shields SD, Ahn HS, Yang Y, et al. Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system. Pain. 2012 Oct;153(10):2017-30. doi: 10.1016/j.pain.2012.04.022.Shields SD, Ahn HS, Yang Y, et al. Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system. Pain. 2012 Oct;153(10):2017-30. doi: 10.1016/j.pain.2012.04.022.Renganathan M, Cummins TR, Waxman SG Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons. J Neurophysiol. 2001 Aug; 86(2):629-40. PMID:11495938Renganathan M, Cummins TR, Waxman SG Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons. J Neurophysiol. 2001 Aug; 86(2):629-40. PMID:11495938Rush AM, Dib-Hajj SD, Liu S, et al. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci U S A. 2006 May 23; 103(21):8245-50. doi: 10.1073/pnas.0602813103Rush AM, Dib-Hajj SD, Liu S, et al. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci U S A. 2006 May 23; 103(21):8245-50. doi: 10.1073/pnas.0602813103Abrahamsen B, Zhao J, Asante CO, et al. The cell and molecular basis of mechanical, cold, and inflammatory pain. Science 2008;321(5889):702-5. doi:10.1126/science.1156916Abrahamsen B, Zhao J, Asante CO, et al. The cell and molecular basis of mechanical, cold, and inflammatory pain. Science 2008;321(5889):702-5. doi:10.1126/science.1156916Zimmermann K, Leffler A, Babes A, et al. Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature. 2007 Jun 14; 447(7146):855-8. doi:10.1038/nature05880Zimmermann K, Leffler A, Babes A, et al. Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature. 2007 Jun 14; 447(7146):855-8. doi:10.1038/nature05880Akopian AN, Souslova V, England S, et al. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci 1999;2(6):541-8. doi:10.1038/9195Akopian AN, Souslova V, England S, et al. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci 1999;2(6):541-8. doi:10.1038/9195Laird JM, Souslova V, Wood JN, Cervero F. Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice. J Neurosci 2002;22(19):8352-6. PMID:12351708Laird JM, Souslova V, Wood JN, Cervero F. Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice. J Neurosci 2002;22(19):8352-6. PMID:12351708Lai J, Gold MS, Kim CS, et al. Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 2002;95(1-2):143-52. PMID:11790477Lai J, Gold MS, Kim CS, et al. Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 2002;95(1-2):143-52. PMID:11790477Roza C, Laird JM, Souslova V, et al. The tetrodotoxin-resistant Na+ channel Nav1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J Physiol 2003;550(Pt:921-6. doi:10.1113/jphysiol.2003.046110Roza C, Laird JM, Souslova V, et al. The tetrodotoxin-resistant Na+ channel Nav1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J Physiol 2003;550(Pt:921-6. doi:10.1113/jphysiol.2003.046110Faber CG, Lauria G, Merkies IS, et al. Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19444-9. doi: 10.1073/pnas.1216080109Faber CG, Lauria G, Merkies IS, et al. Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19444-9. doi: 10.1073/pnas.1216080109Duan G, Han C, Wang Q et al. A SCN10A SNP biases human pain sensitivity. Mol Pain. 2016 Sep 2;12 pii: 1744806916666083 doi:10.1177/1744806916666083Duan G, Han C, Wang Q et al. A SCN10A SNP biases human pain sensitivity. Mol Pain. 2016 Sep 2;12 pii: 1744806916666083 doi:10.1177/1744806916666083Rugiero F, Mistry M, Sage D, et al. Selective expression of a persistent tetrodotoxin-resistant Na+ current and NaV1.9 subunit in myenteric sensory neurons. J Neurosci. 2003 Apr 1; 23(7):2715-25. PMID:12684457Rugiero F, Mistry M, Sage D, et al. Selective expression of a persistent tetrodotoxin-resistant Na+ current and NaV1.9 subunit in myenteric sensory neurons. J Neurosci. 2003 Apr 1; 23(7):2715-25. PMID:12684457Fang X, Djouhri L, McMullan S, et al. Intense isolectin-B4 binding in rat dorsal root ganglion neurons distinguishes C-fiber nociceptors with broad action potentials and high Nav1.9 expression. J Neurosci. 2006 Jul 5; 26(27):7281-92. doi: 10.1523/JNEUROSCI.1072-06.2006Fang X, Djouhri L, McMullan S, et al. Intense isolectin-B4 binding in rat dorsal root ganglion neurons distinguishes C-fiber nociceptors with broad action potentials and high Nav1.9 expression. J Neurosci. 2006 Jul 5; 26(27):7281-92. doi: 10.1523/JNEUROSCI.1072-06.2006Padilla F, Couble ML, Coste B, et al. Expression and localization of the Nav1.9 sodium channel in enteric neurons and in trigeminal sensory endings: implication for intestinal reflex function and orofacial pain. Mol Cell Neurosci. 2007 May; 35(1):138-52. doi:10.1016/j.mcn.2007.02.008Padilla F, Couble ML, Coste B, et al. Expression and localization of the Nav1.9 sodium channel in enteric neurons and in trigeminal sensory endings: implication for intestinal reflex function and orofacial pain. Mol Cell Neurosci. 2007 May; 35(1):138-52. doi:10.1016/j.mcn.2007.02.008Dib-Hajj SD, Tyrrell L, Black JA, Waxman SG NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy. Proc Natl Acad Sci U S A. 1998 Jul 21; 95(15):8963-8. PMCID:PMC21185Dib-Hajj SD, Tyrrell L, Black JA, Waxman SG NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy. Proc Natl Acad Sci U S A. 1998 Jul 21; 95(15):8963-8. PMCID:PMC21185Ostman JA, Nassar MA, Wood JN, Baker MD. GTP up-regulated persistent Na+ current and enhanced nociceptor excitability require NaV1.9. J Physiol 2008;586(4):1077-87. doi:10.1113/jphysiol.2007.147942Ostman JA, Nassar MA, Wood JN, Baker MD. GTP up-regulated persistent Na+ current and enhanced nociceptor excitability require NaV1.9. J Physiol 2008;586(4):1077-87. doi:10.1113/jphysiol.2007.147942Maingret F, Coste B, Padilla F, et al. Inflammatory mediators increase Nav1.9 current and excitability in nociceptors through a coincident detection mechanism. J Gen Physiol. 2008;131(3):211-25. doi:10.1085/jgp.200709935Maingret F, Coste B, Padilla F, et al. Inflammatory mediators increase Nav1.9 current and excitability in nociceptors through a coincident detection mechanism. J Gen Physiol. 2008;131(3):211-25. doi:10.1085/jgp.200709935Ritter AM, Martin WJ, Thorneloe KS. The voltage-gated sodium channel Nav1.9 is required for inflammation-based urinary bladder dysfunction. Neurosci Lett. 2009;452(1):28-32 doi:10.1016/j.neulet.2008.12.051Ritter AM, Martin WJ, Thorneloe KS. The voltage-gated sodium channel Nav1.9 is required for inflammation-based urinary bladder dysfunction. Neurosci Lett. 2009;452(1):28-32 doi:10.1016/j.neulet.2008.12.051Leo S, D’Hooge R, Meert T. Exploring the role of nociceptor-specific sodium channels in pain transmission using Nav1.8 and Nav1.9 knockout mice. Behav Brain Res. 2010;208(1):149-57. doi: 10.1016/j.bbr.2009.11.023Leo S, D’Hooge R, Meert T. Exploring the role of nociceptor-specific sodium channels in pain transmission using Nav1.8 and Nav1.9 knockout mice. Behav Brain Res. 2010;208(1):149-57. doi: 10.1016/j.bbr.2009.11.023Huang J, Han C, Estacion M, et al. Gain-of-function mutations in sodium channel Na(v)1.9 in painful neuropathy Brain. 2014 Jun;137(Pt 6):1627-42. doi:10.1093/brain/awu079Huang J, Han C, Estacion M, et al. Gain-of-function mutations in sodium channel Na(v)1.9 in painful neuropathy Brain. 2014 Jun;137(Pt 6):1627-42. doi:10.1093/brain/awu079Han C, Yang Y, de Greef BTA et al. The Domain II S4-S5 Linker in Nav1.9: A Missense Mutation Enhances Activation, Impairs Fast Inactivation, and Produces Human Painful Neuropathy. Neuromolecular Med. 2015 Jun;17(2):158-69 doi: 10.1007/s12017-015-8347-9Han C, Yang Y, de Greef BTA et al. The Domain II S4-S5 Linker in Nav1.9: A Missense Mutation Enhances Activation, Impairs Fast Inactivation, and Produces Human Painful Neuropathy. Neuromolecular Med. 2015 Jun;17(2):158-69 doi: 10.1007/s12017-015-8347-9Zhang XY, Wen J, Yang W et al. Gain of-Function mutations in SCN11A cause familial episodic pain. Am J Hum Genet 2013;93:957-66. doi: 10.1016/j.ajhg.2013.09.016Zhang XY, Wen J, Yang W et al. Gain of-Function mutations in SCN11A cause familial episodic pain. Am J Hum Genet 2013;93:957-66. doi: 10.1016/j.ajhg.2013.09.016Spillane J, Kullmann, DM, Hanna MG. Genetic neurological channelopathies: molecular genetics and clinical phenotypes. J Neurol Neurosurg Psychiatry. 2016 Jan;87(1):37-48. doi:10.1136/jnnp-2015-311233Spillane J, Kullmann, DM, Hanna MG. Genetic neurological channelopathies: molecular genetics and clinical phenotypes. J Neurol Neurosurg Psychiatry. 2016 Jan;87(1):37-48. doi:10.1136/jnnp-2015-311233

The authors declare that there are no conflicts of interest present.