Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The physiological function of different voltage-gated sodium channels in pain

Abstract

Evidence from human genetic pain disorders shows that voltage-gated sodium channel α-subtypes Nav1.7, Nav1.8 and Nav1.9 are important in the peripheral signalling of pain. Nav1.7 is of particular interest because individuals with Nav1.7 loss-of-function mutations are congenitally insensitive to acute and chronic pain, and there is considerable hope that phenocopying these effects with a pharmacological antagonist will produce a new class of analgesic drug. However, studies in these rare individuals do not reveal how and where voltage-gated sodium channels contribute to pain signalling, which is of critical importance for drug development. More than a decade of research utilizing rodent genetic models and pharmacological tools to study voltage-gated sodium channels in pain has begun to unravel the role of different subtypes. Here, we review the contribution of individual channel subtypes in three key physiological processes necessary for transmission of sensory information to the CNS: transduction of stimuli at peripheral nerve terminals, axonal transmission of action potentials and neurotransmitter release from central terminals. These data suggest that drugs seeking to recapitulate the analgesic effects of loss of function of Nav1.7 will need to be brain-penetrant — which most of those developed to date are not.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Summary of the contribution of different Navs to neuronal activity in nociceptive neurons innervating somatic and visceral tissue.

References

  1. 1.

    Calatayud, J. & Gonzalez, A. History of the development and evolution of local anesthesia since the coca leaf. Anesthesiology 98, 1503–1508 (2003).

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Koller, C. On the use of cocaine for producing anæsthesia on the eye. Lancet 124, 990–992 (1884).

    Article  Google Scholar 

  3. 3.

    Vaso, A. et al. Peripheral nervous system origin of phantom limb pain. Pain 155, 1384–1391 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Haroutounian, S. et al. Primary afferent input critical for maintaining spontaneous pain in peripheral neuropathy. Pain 155, 1272–1279 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Hodgkin, A. L. & Huxley, A. F. Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J. Physiol. 116, 449–472 (1952).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Hodgkin, A. L. & Huxley, A. F. The dual effect of membrane potential on sodium conductance in the giant axon of Loligo. J. Physiol. 116, 497–506 (1952).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Xiong, Z. & Strichartz, G. R. Inhibition by local anesthetics of Ca2+ channels in rat anterior pituitary cells. Eur. J. Pharmacol. 363, 81–90 (1998).

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Sugiyama, K. & Muteki, T. Local anesthetics depress the calcium current of rat sensory neurons in culture. Anesthesiology 80, 1369–1378 (1994).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Jaffe, R. A. & Rowe, M. A. Differential nerve block. Direct measurements on individual myelinated and unmyelinated dorsal root axons. Anesthesiology 84, 1455–1464 (1996).

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Fink, B. R. & Cairns, A. M. Differential peripheral axon block with lidocaine: unit studies in the cervical vagus nerve. Anesthesiology 59, 182–186 (1983).

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Papadatos, G. A. et al. Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a. Proc. Natl Acad. Sci. USA 99, 6210–6215 (2002).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Alsaloum, M., Higerd, G. P., Effraim, P. R. & Waxman, S. G. Status of peripheral sodium channel blockers for non-addictive pain treatment. Nat. Rev. Neurol. 16, 689–705 (2020).

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Hull, J. M. & Isom, L. L. Voltage-gated sodium channel β subunits:tThe power outside the pore in brain development and disease. Neuropharmacology 132, 43–57 (2018).

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Ruhlmann, A. H. et al. Uncoupling sodium channel dimers restores the phenotype of a pain-linked Nav 1.7 channel mutation. Br. J. Pharmacol. 177, 4481–4496 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 15.

    Clatot, J. et al. Voltage-gated sodium channels assemble and gate as dimers. Nat. Commun. 8, 2077 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. 16.

    Kanellopoulos, A. H. et al. Mapping protein interactions of sodium channel NaV1.7 using epitope-tagged gene-targeted mice. EMBO J. 37, 427–445 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Dustrude, E. T., Wilson, S. M., Ju, W., Xiao, Y. & Khanna, R. CRMP2 protein SUMOylation modulates NaV1.7 channel trafficking. J. Biol. Chem. 288, 24316–24331 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Alsaloum, M. et al. A gain-of-function sodium channel β2-subunit mutation in painful diabetic neuropathy. Mol. Pain 15, 1744806919849802 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014.e22 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Blair, N. T. & Bean, B. P. 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 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Dib-Hajj, S. D. et al. Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Brain 128, 1847–1854 (2005).

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Faber, C. G. et al. Gain-of-function Nav1.8 mutations in painful neuropathy. Proc. Natl Acad. Sci. USA 109, 19444–19449 (2012).

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Huang, J. et al. Gain-of-function mutations in sodium channel Na(v)1.9 in painful neuropathy. Brain 137, 1627–1642 (2014).

    PubMed  Article  Google Scholar 

  24. 24.

    Cox, J. J. et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 444, 894–898 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Leipold, E. et al. A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nat. Genet. 45, 1399–1404 (2013). This paper reports on individuals with Nav1.9 mutations who are congenitally insensitive to pain and how these mutations are proposed to cause pain insensitivity.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Goldberg, Y. P. et al. Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations. Clin. Genet. 71, 311–319 (2007).

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    McDermott, L. A. et al. Defining the functional role of NaV1.7 in human nociception. Neuron 101, 905–919.e8 (2019). This paper provides a clinical evaluation of three individuals who are insensitive to pain owing to Nav1.7 mutations, and provides a functional examination of their stem-cell derived nociceptors.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Weiss, J. et al. Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature 472, 186–190 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Dib-Hajj, S. D. et al. Paroxysmal extreme pain disorder M1627K mutation in human Nav1.7 renders DRG neurons hyperexcitable. Mol. Pain 4, 37 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30.

    Fertleman, C. R. et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron 52, 767–774 (2006).

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Orstavik, K. & Jorum, E. Microneurographic findings of relevance to pain in patients with erythromelalgia and patients with diabetic neuropathy. Neurosci. Lett. 470, 180–184 (2010).

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Namer, B. et al. Specific changes in conduction velocity recovery cycles of single nociceptors in a patient with erythromelalgia with the I848T gain-of-function mutation of Nav1.7. Pain 156, 1637–1646 (2015).

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Indo, Y. Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Hum. Mutat. 18, 462–471 (2001).

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Einarsdottir, E. et al. A mutation in the nerve growth factor β gene (NGFB) causes loss of pain perception. Hum. Mol. Genet. 13, 799–805 (2004).

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Nilsen, K. B. et al. Two novel SCN9A mutations causing insensitivity to pain. Pain 143, 155–158 (2009).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Klein, C. J. et al. Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia. J. Neurol. Neurosurg. Psychiatry 84, 386–391 (2013).

    PubMed  Article  Google Scholar 

  37. 37.

    Marchi, M. et al. A novel SCN9A splicing mutation in a compound heterozygous girl with congenital insensitivity to pain, hyposmia and hypogeusia. J. Peripher. Nerv. Syst. 23, 202–206 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Emery, E. C. et al. Novel SCN9A mutations underlying extreme pain phenotypes: unexpected electrophysiological and clinical phenotype correlations. J. Neurosci. 35, 7674–7681 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Sun, J. et al. Novel SCN9A missense mutations contribute to congenital insensitivity to pain: unexpected correlation between electrophysiological characterization and clinical phenotype. Mol. Pain 16, 1744806920923881 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Zhang, X. Y. et al. Gain-of-function mutations in SCN11A cause familial episodic pain. Am. J. Hum. Genet. 93, 957–966 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Dib-Hajj, S. D. et al. Two tetrodotoxin-resistant sodium channels in human dorsal root ganglion neurons. FEBS Lett. 462, 117–120 (1999).

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Woods, C. G., Babiker, M. O. E., Horrocks, I., Tolmie, J. & Kurth, I. The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P. Eur. J. Hum. Genet. 23, 561–563 (2015).

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Huang, J. et al. Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability. J. Clin. Invest. 127, 2805–2814 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Salvatierra, J. et al. A disease mutation reveals a role for NaV1.9 in acute itch. J. Clin. Invest. 128, 5434–5447 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Dib-Hajj, S., Black, J. A., Cummins, T. R. & Waxman, S. G. NaN/Nav1.9: a sodium channel with unique properties. Trends Neurosci. 25, 253–259 (2002).

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Fang, X. 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. 26, 7281–7292 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Han, C. et al. The G1662S NaV1.8 mutation in small fibre neuropathy: impaired inactivation underlying DRG neuron hyperexcitability. J. Neurol. Neurosurg. Psychiatry 85, 499–505 (2014).

    PubMed  Article  Google Scholar 

  48. 48.

    Huang, J. et al. Small-fiber neuropathy Nav1.8 mutation shifts activation to hyperpolarized potentials and increases excitability of dorsal root ganglion neurons. J. Neurosci. 33, 14087–14097 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Duan, G. et al. A SCN10A SNP biases human pain sensitivity. Mol. Pain https://doi.org/10.1177/1744806916666083 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Behr, E. R. et al. Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study. Cardiovasc. Res. 106, 520–529 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Hu, D. et al. Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome. J. Am. Coll. Cardiol. 64, 66–79 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Verkerk, A. O. et al. Functional Nav1.8 channels in intracardiac neurons: the link between SCN10A and cardiac electrophysiology. Circ. Res. 111, 333–343 (2012).

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Yang, T. et al. Blocking Scn10a channels in heart reduces late sodium current and is antiarrhythmic. Circ. Res. 111, 322–332 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    van den Boogaard, M. et al. A common genetic variant within SCN10A modulates cardiac SCN5A expression. J. Clin. Invest. 124, 1844–1852 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  55. 55.

    Dichgans, M. et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366, 371–377 (2005).

    CAS  PubMed  Article  Google Scholar 

  56. 56.

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

    PubMed  Article  Google Scholar 

  57. 57.

    Tanaka, B. S. et al. A gain-of-function mutation in Nav1.6 in a case of trigeminal neuralgia. Mol. Med. 22, 338–348 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Trudeau, M. M., Dalton, J. C., Day, J. W., Ranum, L. P. & Meisler, M. H. Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation. J. Med. Genet. 43, 527–530 (2006).

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Wagnon, J. L. et al. Loss-of-function variants of SCN8A in intellectual disability without seizures. Neurol. Genet. 3, e170 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Wengert, E. R. et al. Biallelic inherited SCN8A variants, a rare cause of SCN8A-related developmental and epileptic encephalopathy. Epilepsia 60, 2277–2285 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Mantegazza, M. et al. Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures. Proc. Natl Acad. Sci. USA 102, 18177–18182 (2005).

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Lossin, C. et al. Epilepsy-associated dysfunction in the voltage-gated neuronal sodium channel SCN1A. J. Neurosci. 23, 11289–11295 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Bennett, D. L., Clark, A. J., Huang, J., Waxman, S. G. & Dib-Hajj, S. D. The role of voltage-gated sodium channels in pain signaling. Physiol. Rev. 99, 1079–1151 (2019).

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Cummins, T. R., Howe, J. R. & Waxman, S. G. Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel. J. Neurosci. 18, 9607–9619 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Herzog, R. I., Cummins, T. R., Ghassemi, F., Dib-Hajj, S. D. & Waxman, S. G. Distinct repriming and closed-state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons. J. Physiol. 551, 3–50 (2003).

    Article  CAS  Google Scholar 

  66. 66.

    Hockley, J. R. et al. Visceral and somatic pain modalities reveal NaV 1.7-independent visceral nociceptive pathways. J. Physiol. 595, 2661–2679 (2017). This paper examines the contribution of Nav1.7 to transduction at visceral afferent terminals.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Kornecook, T. J. et al. Pharmacologic characterization of AMG8379, a potent and selective small molecule sulfonamide antagonist of the voltage-gated sodium channel NaV1.7. J. Pharmacol. Exp. Ther. 362, 146–160 (2017).

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    MacDonald, D. I. et al. The mechanism of analgesia in Nav1.7 null mutants. bioRxiv https://doi.org/10.1101/2020.06.01.127183 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Touska, F. et al. Heat-resistant action potentials require TTX-resistant sodium channels NaV1.8 and NaV1.9. J. Gen. Physiol. 150, 1125–1144 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Zimmermann, K. et al. Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature 447, 855–858 (2007).

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Jonas, R. et al. TTX-resistant sodium channels functionally separate silent from polymodal C-nociceptors. Front. Cell Neurosci. 14, 13 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Feng, B., Zhu, Y., La, J. H., Wills, Z. P. & Gebhart, G. F. Experimental and computational evidence for an essential role of NaV1.6 in spike initiation at stretch-sensitive colorectal afferent endings. J. Neurophysiol. 113, 2618–2634 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Kollarik, M. et al. Different role of TTX-sensitive voltage-gated sodium channel (NaV 1) subtypes in action potential initiation and conduction in vagal airway nociceptors. J. Physiol. 596, 1419–1432 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Ru, F. et al. Stimulus intensity-dependent recruitment of NaV1 subunits in action potential initiation in nerve terminals of vagal C-fibers innervating the esophagus. Am. J. Physiol. Gastrointest. Liver Physiol. 319, G443–G453 (2020).

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Jurcakova, D. et al. Voltage-gated sodium channels regulating action potential generation in itch-, nociceptive-, and low-threshold mechanosensitive cutaneous C-fibers. Mol. Pharmacol. 94, 1047–1056 (2018).

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Israel, M. R. et al. NaV1.6 regulates excitability of mechanosensitive sensory neurons. J. Physiol. 597, 3751–3768 (2019).

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Osteen, J. D. et al. Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain. Nature 534, 494–499 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Persson, A. K. et al. Sodium-calcium exchanger and multiple sodium channel isoforms in intra-epidermal nerve terminals. Mol. Pain 6, 84 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Chen, L. et al. Conditional knockout of NaV1.6 in adult mice ameliorates neuropathic pain. Sci. Rep. 8, 3845 (2018). This study demonstrates that Nav subtypes that are not typically associated with pain are involved in the development of neuropathic pain following nerve injury.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. 80.

    Priest, B. T. et al. Contribution of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensory transmission and nociceptive behavior. Proc. Natl Acad. Sci. USA 102, 9382–9387 (2005).

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Cummins, T. R. et al. A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild-type small primary sensory neurons. J. Neurosci. 19, RC43 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Hoffmann, T. et al. Reduced excitability and impaired nociception in peripheral unmyelinated fibers from Nav1.9-null mice. Pain 158, 58–67 (2017).

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Minett, M. S., Eijkelkamp, N. & Wood, J. N. Significant determinants of mouse pain behaviour. PLoS ONE 9, e104458 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. 84.

    Hockley, J. R. et al. Multiple roles for NaV1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease-derived stimuli. Pain 155, 1962–1975 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Renganathan, M., Cummins, T. R. & Waxman, S. G. Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons. J. Neurophysiol. 86, 629–640 (2001).

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Klein, A. H. et al. Sodium channel Nav1.8 underlies TTX-resistant axonal action potential conduction in somatosensory C-fibers of distal cutaneous nerves. J. Neurosci. 37, 5204–5214 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Wilson, M. J. et al. μ-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve. Proc. Natl Acad. Sci. USA 108, 10302–10307 (2011).

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Jeftinija, S. The role of tetrodotoxin-resistant sodium channels of small primary afferent fibers. Brain Res. 639, 125–134 (1994).

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Steffens, H., Eek, B., Trudrung, P. & Mense, S. Tetrodotoxin block of A-fibre afferents from skin and muscle — a tool to study pure C-fibre effects in the spinal cord. Pflug. Arch. Eur. J. Physiol. 445, 607–613 (2003).

    CAS  Article  Google Scholar 

  90. 90.

    Gingras, J. et al. Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain. PLoS ONE 9, e105895 (2014). This paper describes the first global Nav1.7 knockout mouse and the behavioural, anatomical and electrophysiological changes that occur in these animals.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. 91.

    Hoffmann, T. et al. NaV1.7 and pain: contribution of peripheral nerves. Pain 159, 496–506 (2018). This paper provides a detailed examination of the electrophysiological changes that occur in peripheral nerve nociceptors of Nav1.7 knockout mice.

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Schmalhofer, W. A. et al. ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Mol. Pharmacol. 74, 1476–1484 (2008).

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Alexandrou, A. J. et al. Subtype-selective small molecule inhibitors reveal a fundamental role for Nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release. PLoS ONE 11, e0152405–e0152405 (2016). This paper provides an in vitro and ex vivo examination of Nav1.7 function in nociceptors using selective pharmacological inhibitors of the channel.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  94. 94.

    Pinto, V., Derkach, V. A. & Safronov, B. V. Role of TTX-sensitive and TTX-resistant sodium channels in Aδ- and C-fiber conduction and synaptic transmission. J. Neurophysiol. 99, 617–628 (2008).

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Lambertz, D., Hoheisel, U. & Mense, S. Distribution of synaptic field potentials induced by TTX-resistant skin and muscle afferents in rat spinal segments L4 and L5. Neurosci. Lett. 409, 14–18 (2006).

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Quasthoff, S., Grosskreutz, J., Schroder, J. M., Schneider, U. & Grafe, P. Calcium potentials and tetrodotoxin-resistant sodium potentials in unmyelinated C fibres of biopsied human sural nerve. Neuroscience 69, 955–965 (1995).

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Grosskreutz, J., Quasthoff, S., Kuhn, M. & Grafe, P. Capsaicin blocks tetrodotoxin-resistant sodium potentials and calcium potentials in unmyelinated C fibres of biopsied human sural nerve in vitro. Neurosci. Lett. 208, 49–52 (1996).

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Torebjork, H. E., Schady, W. & Ochoa, J. L. A new method for demonstration of central effects of analgesic agents in man. J. Neurol. Neurosurg. Psychiatry 47, 862–869 (1984).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Caldwell, J. H., Schaller, K. L., Lasher, R. S., Peles, E. & Levinson, S. R. Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses. Proc. Natl Acad. Sci. USA 97, 5616–5620 (2000).

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Black, J. A., Renganathan, M. & Waxman, S. G. Sodium channel Na(v)1.6 is expressed along nonmyelinated axons and it contributes to conduction. Brain Res. Mol.Brain Res. 105, 19–28 (2002).

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Muroi, Y. et al. Selective silencing of Na(V)1.7 decreases excitability and conduction in vagal sensory neurons. J. Physiol. 589, 5663–5676 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Minett, M. S. et al. Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons. Nat. Commun. 3, 791 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. 103.

    Sugiura, Y., Lee, C. L. & Perl, E. R. Central projections of identified, unmyelinated (C) afferent fibers innervating mammalian skin. Science 234, 358–361 (1986).

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Sugiura, Y., Terui, N. & Hosoya, Y. Difference in distribution of central terminals between visceral and somatic unmyelinated (C) primary afferent fibers. J. Neurophysiol. 62, 834–840 (1989).

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Rethelyi, M. Preterminal and terminal axon arborizations in the substantia gelatinosa of cat’s spinal cord. J. Comp. Neurol. 172, 511–521 (1977).

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Sugiura, Y. et al. Quantitative analysis of central terminal projections of visceral and somatic unmyelinated (C) primary afferent fibers in the guinea pig. J. Comp. Neurol. 332, 315–325 (1993).

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Luscher, C., Streit, J., Quadroni, R. & Luscher, H. R. Action potential propagation through embryonic dorsal root ganglion cells in culture. I. Influence of the cell morphology on propagation properties. J. Neurophysiol. 72, 622–633 (1994).

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Streit, J., Luscher, C. & Luscher, H. R. Depression of postsynaptic potentials by high-frequency stimulation in embryonic motoneurons grown in spinal cord slice cultures. J. Neurophysiol. 68, 1793–1803 (1992).

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Luscher, H. R. & Shiner, J. S. Simulation of action potential propagation in complex terminal arborizations. Biophys. J. 58, 1389–1399 (1990).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Luscher, H. R. & Shiner, J. S. Computation of action potential propagation and presynaptic bouton activation in terminal arborizations of different geometries. Biophys. J. 58, 1377–1388 (1990).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Stockbridge, N. & Stockbridge, L. L. Differential conduction at axonal bifurcations. I. Effect of electrotonic length. J. Neurophysiol. 59, 1277–1285 (1988).

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Bao, J., Li, J. J. & Perl, E. R. Differences in Ca2+ channels governing generation of miniature and evoked excitatory synaptic currents in spinal laminae I and II. J. Neurosci. 18, 8740–8750 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Alles, S. R. A. et al. Sensory neuron-derived NaV1.7 contributes to dorsal horn neuron excitability. Sci. Adv. 6, eaax4568 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Medvedeva, Y. V., Kim, M. S., Schnizler, K. & Usachev, Y. M. Functional tetrodotoxin-resistant Na+ channels are expressed presynaptically in rat dorsal root ganglia neurons. Neuroscience 159, 559–569 (2009).

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Gu, J. G. & MacDermott, A. B. Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses. Nature 389, 749–753 (1997).

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Vysokov, N., McMahon, S. B. & Raouf, R. The role of NaV channels in synaptic transmission after axotomy in a microfluidic culture platform. Sci. Rep. 9, 12915 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  117. 117.

    McDonnell, A. et al. Efficacy of the Nav1.7 blocker PF-05089771 in a randomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy. Pain 159, 1465–1476 (2018).

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Siebenga, P. et al. Lack of detection of the analgesic properties of PF-05089771, a selective Nav 1.7 inhibitor, using a battery of pain models in healthy subjects. Clin. Transl. Sci. 13, 318–324 (2020).

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Minett, M. S. et al. Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7. Nat. Commun. 6, 8967 (2015). This study details the proposed mechanism that endogenous opioids are responsible for Nav1.7 loss-of-function analgesia.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Pereira, V. et al. Analgesia linked to Nav1.7 loss of function requires μ- and δ-opioid receptors. Wellcome Open Res. 3, 101 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  121. 121.

    Isensee, J. et al. Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in Nav1.7 knockout mice. Sci Signal 10, eaah4874 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  122. 122.

    Chen, L. et al. Pharmacological characterization of a rat Nav1.7 loss-of-function model with insensitivity to pain. Pain 161, 1350–1360 (2020). This study reports that endogenous opioids are not responsible for analgesia in a rat Nav1.7 loss-of-function insensitivity to pain model.

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Gold, M. S., Reichling, D. B., Shuster, M. J. & Levine, J. D. Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors. Proc. Natl Acad. Sci. USA 93, 1108–1112 (1996).

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Black, J. A., Liu, S., Tanaka, M., Cummins, T. R. & Waxman, S. G. Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain. 108, 237–247 (2004).

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Docherty, R. J. & Farrag, K. J. The effect of dibutyryl cAMP on tetrodotoxin-sensitive and -resistant voltage-gated sodium currents in rat dorsal root ganglion neurons and the consequences for their sensitivity to lidocaine. Neuropharmacology 51, 1047–1057 (2006).

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Gold, M. S., Levine, J. D. & Correa, A. M. Modulation of TTX-R/Na by PKC and PKA and their role in PGE2-induced sensitization of rat sensory neurons in vitro. J. Neurosci. 18, 10345–10355 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    Akopian, A. N. et al. Trans-splicing of a voltage-gated sodium channel is regulated by nerve growth factor. FEBS Lett. 445, 177–182 (1999).

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Akin, E. J. et al. Building sensory axons: delivery and distribution of NaV1.7 channels and effects of inflammatory mediators. Sci. Adv. 5, eaax4755 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Akopian, A. N. et al. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat. Neurosci. 2, 541–548 (1999).

    CAS  PubMed  Article  Google Scholar 

  130. 130.

    Kerr, B. J., Souslova, V., McMahon, S. B. & Wood, J. N. A role for the TTX-resistant sodium channel Nav 1.8 in NGF-induced hyperalgesia, but not neuropathic pain. Neuro Report 12, 3077–3080 (2001).

    CAS  Google Scholar 

  131. 131.

    Waxman, S. G., Kocsis, J. D. & Black, J. A. Type III sodium channel mRNA is expressed in embryonic but not adult spinal sensory neurons, and is reexpressed following axotomy. J. Neurophysiol. 72, 466–470 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Boucher, T. J. et al. Potent analgesic effects of GDNF in neuropathic pain states. Science 290, 124–127 (2000).

    CAS  PubMed  Article  Google Scholar 

  133. 133.

    Renthal, W. et al. Transcriptional reprogramming of distinct peripheral sensory neuron subtypes after axonal injury. Neuro 108, 128–144 (2020).

    CAS  Google Scholar 

  134. 134.

    Nguyen, M. Q., Le Pichon, C. E. & Ryba, N. Stereotyped transcriptomic transformation of somatosensory neurons in response to injury. eLife 8, e49679 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Nassar, M. A. et al. Nerve injury induces robust allodynia and ectopic discharges in Nav1.3 null mutant mice. Mol. Pain 2, 33 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  136. 136.

    Devor, M., Govrin-Lippmann, R. & Angelides, K. Na+ channel immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J.Neurosci. 13, 1976–1992 (1993).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Devor, M., Wall, P. D. & Catalan, N. Systemic lidocaine silences ectopic neuroma and DRG discharge without blocking nerve conduction. Pain 48, 261–268 (1992).

    PubMed  Article  Google Scholar 

  138. 138.

    Welk, E., Leah, J. D. & Zimmermann, M. Characteristics of A- and C-fibers ending in a sensory nerve neuroma in the rat. J. Neurophysiol. 63, 759–766 (1990).

    CAS  PubMed  Article  Google Scholar 

  139. 139.

    Rivera, L., Gallar, J., Pozo, M. A. & Belmonte, C. Responses of nerve fibres of the rat saphenous nerve neuroma to mechanical and chemical stimulation: an in vitro study. J. Physiol. 527, 305–313 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    Black, J. A., Nikolajsen, L., Kroner, K., Jensen, T. S. & Waxman, S. G. Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann. Neurol. 64, 644–653 (2008).

    PubMed  Article  Google Scholar 

  141. 141.

    Roza, C., Laird, J. M., Souslova, V., Wood, J. N. & Cervero, F. 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 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Matzner, O. & Devor, M. Hyperexcitability at sites of nerve injury depends on voltage-sensitive Na+ channels. J. Neurophysiol. 72, 349–359 (1994).

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    Omana-Zapata, I., Khabbaz, M. A., Hunter, J. C., Clarke, D. E. & Bley, K. R. Tetrodotoxin inhibits neuropathic ectopic activity in neuromas, dorsal root ganglia and dorsal horn neurons. Pain 72, 41–49 (1997).

    CAS  PubMed  Article  Google Scholar 

  144. 144.

    Gold, M. S. et al. Redistribution of NaV1.8 in uninjured axons enables neuropathic pain. J. Neurosci. 23, 158–166 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Nassar, M. A., Levato, A., Stirling, L. C. & Wood, J. N. Neuropathic pain develops normally in mice lacking both Nav1.7 and Nav1.8. Mol. Pain 1, 24 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  146. 146.

    Minett, M. S. et al. Pain without nociceptors? Nav1.7-independent pain mechanisms. Cell Rep. 6, 301–312 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    Knudsen, L. F., Terkelsen, A. J., Drummond, P. D. & Birklein, F. Complex regional pain syndrome: a focus on the autonomic nervous system. Clin. Auton. Res. 29, 457–467 (2019).

    PubMed  Article  Google Scholar 

  148. 148.

    Wheeler, D. W., Lee, M. C., Harrison, E. K., Menon, D. K. & Woods, C. G. Case report: neuropathic pain in a patient with congenital insensitivity to pain. F1000Res 3, 135 (2014).

    PubMed  Article  Google Scholar 

  149. 149.

    Price, N. et al. Safety and efficacy of a topical sodium channel inhibitor (TV-45070) in patients with postherpetic neuralgia (PHN): a randomized, controlled, proof-of-concept, crossover study, with a subgroup analysis of the Nav1.7 R1150W genotype. Clin. J. Pain 33, 310–318 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  150. 150.

    Hockley, J. R. et al. P2Y receptors sensitize mouse and human colonic nociceptors. J. Neurosci. 36, 2364–2376 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    Shields, S. D. et al. Insensitivity to pain upon adult-onset deletion of Nav1.7 or its blockade with selective inhibitors. J. Neurosci. 38, 10180–10201 (2018). This paper shows that adult-onset deletion of Nav1.7 produces analgesia in mice, suggesting that Nav1.7 loss-of-function analgesia is not developmental.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Branco, T. et al. Near-perfect synaptic integration by Nav1.7 in hypothalamic neurons regulates body weight. Cell 165, 1749–1761 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. 153.

    Grubinska, B. et al. Rat NaV1.7 loss-of-function genetic model: deficient nociceptive and neuropathic pain behavior with retained olfactory function and intra-epidermal nerve fibers. Mol. Pain 15, 1744806919881846 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Nagi, S. S. et al. An ultrafast system for signaling mechanical pain in human skin. Sci. Adv. 5, eaaw1297 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Abrahamsen, B. et al. The cell and molecular basis of mechanical, cold, and inflammatory pain. Science 321, 702–705 (2008).

    CAS  PubMed  Article  Google Scholar 

  156. 156.

    Tsukamoto, T. et al. Differential binding of tetrodotoxin and its derivatives to voltage-sensitive sodium channel subtypes (Nav 1.1 to Nav 1.7). Br. J. Pharmacol. 174, 3881–3892 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. 157.

    Bricelj, V. M. et al. Sodium channel mutation leading to saxitoxin resistance in clams increases risk of PSP. Nature 434, 763–767 (2005).

    CAS  PubMed  Article  Google Scholar 

  158. 158.

    Sangameswaran, L. et al. A novel tetrodotoxin-sensitive, voltage-gated sodium channel expressed in rat and human dorsal root ganglia. J. Biol. Chem. 272, 14805–14809 (1997).

    CAS  PubMed  Article  Google Scholar 

  159. 159.

    Akopian, A. N., Sivilotti, L. & Wood, J. N. A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379, 257–262 (1996).

    CAS  PubMed  Article  Google Scholar 

  160. 160.

    Jarvis, M. F. et al. 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 (2007).

    CAS  PubMed  Article  Google Scholar 

  161. 161.

    Payne, C. E. et al. A novel selective and orally bioavailable Nav 1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability. Br. J. Pharmacol. 172, 2654–2670 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Lin, Z., Santos, S., Padilla, K., Printzenhoff, D. & Castle, N. A. Biophysical and pharmacological characterization of Nav1.9 voltage dependent sodium channels stably expressed in HEK-293 cells. PLoS ONE 11, e0161450 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  163. 163.

    Chisholm, K. I., Khovanov, N., Lopes, D. M., La Russa, F. & McMahon, S. B. Large scale in vivo recording of sensory neuron activity with GCaMP6. eNeuro https://doi.org/10.1523/eneuro.0417-17.2018 (2018). This study demonstrates how in vivo optical imaging techniques can be used to further our understanding of peripheral pain signalling mechanisms.

    Article  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Wang, F. et al. Sensory afferents use different coding strategies for heat and cold. Cell Rep. 23, 2001–2013 (2018).

    CAS  PubMed  Article  Google Scholar 

  165. 165.

    Luiz, A. P. et al. Cold sensing by NaV1.8-positive and NaV1.8-negative sensory neurons. Proc. Natl Acad. Sci. USA 116, 3811–3816 (2019).

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

The authors thank E. Stevens for useful comments on the manuscript.

Author information

Affiliations

Authors

Contributions

G.G. and S.B.M. contributed equally to this work.

Corresponding authors

Correspondence to George Goodwin or Stephen B. McMahon.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Neuroscience thanks Ewan St. John Smith and the other anonymous reviewer(s) for their contribution to the peer review of this manuscript.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Paroxysmal extreme pain disorder

A type of peripheral neuropathy characterized by skin redness, warmth and attacks of severe pain in various parts of the body.

Pruritus

Severe itching of the skin.

Brugada syndrome

A genetic disorder that can cause a dangerous irregular heartbeat.

Microneurography

A neurophysiological technique for recording electrical activity from peripheral nerve fibres.

Hyperalgesia

Increased pain from a stimulus that normally provokes pain.

Neuroma

A disorganized growth of nerve fibres at the site of nerve injury.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Goodwin, G., McMahon, S.B. The physiological function of different voltage-gated sodium channels in pain. Nat Rev Neurosci 22, 263–274 (2021). https://doi.org/10.1038/s41583-021-00444-w

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing