NaV1.9: a sodium channel linked to human pain

Article metrics


The voltage-gated sodium channel NaV1.9 is preferentially expressed in nociceptors and has been shown in rodent models to have a major role in inflammatory and neuropathic pain. These studies suggest that by selectively targeting NaV1.9, it might be possible to ameliorate pain without inducing adverse CNS side effects such as sedation, confusion and addictive potential. Three recent studies in humans — two genetic and functional studies in rare genetic disorders, and a third study showing a role for NaV1.9 in painful peripheral neuropathy — have demonstrated that NaV1.9 plays an important part both in regulating sensory neuron excitability and in pain signalling. With this human validation, attention is turning to this channel as a potential therapeutic target for pain.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Distribution of NaV1.9 in primary afferents.
Figure 2: NaV1.9 increases the excitability of DRG neurons.
Figure 3: Schematic diagram of the NaV1.9 channel and locations of substitutions identified in individuals with pain disorders.
Figure 4: Voltage-clamp and current-clamp analyses of NaV1.9 I381T mutant channels.


  1. 1

    Catterall, W. A., Goldin, A. L. & Waxman, S. G. International Union of Pharmacology. XLVII. Nomenclature and structure–function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57, 397–409 (2005).

  2. 2

    Dib-Hajj, S. D., Yang, Y., Black, J. A. & Waxman, S. G. The NaV1.7 sodium channel: from molecule to man. Nat. Rev. Neurosci. 14, 49–62 (2013).

  3. 3

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

  4. 4

    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).

  5. 5

    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).

  6. 6

    Huang, J. et al. Gain-of-function mutations in sodium channel Nav1.9 in painful neuropathy. Brain 137, 1627–1642 (2014).

  7. 7

    Leipold, E. et al. A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nat. Genet. 45, 1399–1404 (2013).

  8. 8

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

  9. 9

    Han, C. 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. 17, 158–169 (2015).

  10. 10

    Dib-Hajj, S. D., Tyrrell, L., Black, J. A. & Waxman, S. G. NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy. Proc. Natl Acad. Sci. USA 95, 8963–8968 (1998).

  11. 11

    Dib-Hajj, S. D. et al. Coding sequence, genomic organization, and conserved chromosomal localization of the mouse gene Scn11a encoding the sodium channel NaN. Genomics 59, 309–318 (1999).

  12. 12

    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).

  13. 13

    Rugiero, F. et al. Selective expression of a persistent tetrodotoxin-resistant Na+ current and NaV1.9 subunit in myenteric sensory neurons. J. Neurosci. 23, 2715–2725 (2003).

  14. 14

    Fang, X. et al. The presence and role of the tetrodotoxin-resistant sodium channel Nav1.9 (NaN) in nociceptive primary afferent neurons. J. Neurosci. 22, 7425–7433 (2002).

  15. 15

    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).

  16. 16

    Amaya, F. et al. The voltage-gated sodium channel Nav1.9 is an effector of peripheral inflammatory pain hypersensitivity. J. Neurosci. 26, 12852–12860 (2006).

  17. 17

    Herzog, R. I., Cummins, T. R. & Waxman, S. G. Persistent TTX-resistant Na+ current affects resting potential and response to depolarization in simulated spinal sensory neurons. J. Neurophysiol. 86, 1351–1364 (2001).

  18. 18

    Braz, J. M., Nassar, M. A., Wood, J. N. & Basbaum, A. I. Parallel “pain” pathways arise from subpopulations of primary afferent nociceptor. Neuron 47, 787–793 (2005).

  19. 19

    Stucky, C. L. & Lewin, G. R. Isolectin B4-positive and -negative nociceptors are functionally distinct. J. Neurosci. 19, 6497–6505 (1999).

  20. 20

    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).

  21. 21

    Santarelli, V. P., Eastwood, A. L., Dougherty, D. A., Horn, R. & Ahern, C. A. A cation-π interaction discriminates among sodium channels that are either sensitive or resistant to tetrodotoxin block. J. Biol. Chem. 282, 8044–8051 (2007).

  22. 22

    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).

  23. 23

    Maruyama, H. et al. Electrophysiological characterization of the tetrodotoxin-resistant Na+ channel, Nav1.9, in mouse dorsal root ganglion neurons. Pflugers Arch. 449, 76–87 (2004).

  24. 24

    Coste, B., Osorio, N., Padilla, F., Crest, M. & Delmas, P. Gating and modulation of presumptive NaV1.9 channels in enteric and spinal sensory neurons. Mol. Cell Neurosci. 26, 123–134 (2004).

  25. 25

    Scroggs, R. S. The distribution of low-threshold TTX-resistant Na+ currents in rat trigeminal ganglion cells. Neuroscience 222, 205–214 (2012).

  26. 26

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

  27. 27

    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).

  28. 28

    Ostman, J. A., Nassar, M. A., Wood, J. N. & Baker, M. D. GTP up-regulated persistent Na+ current and enhanced nociceptor excitability require NaV1.9. J. Physiol. 586, 1077–1087 (2007).

  29. 29

    Baker, M. D., Chandra, S. Y., Ding, Y., Waxman, S. G. & Wood, J. N. GTP-induced tetrodotoxin-resistant Na+ current regulates excitability in mouse and rat small diameter sensory neurones. J. Physiol. 548, 373–382 (2003).

  30. 30

    Harty, T. P. et al. NaV1.7 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 (2006).

  31. 31

    Vasylyev, D. V., Han, C., Zhao, P., Dib-Hajj, S. & Waxman, S. G. Dynamic-clamp analysis of wild-type hNaV1.7 and erythromelalgia mutant channel L858H. J. Neurophysiol. 111, 1429–1443 (2014).

  32. 32

    Copel, C. et al. Activation of neurokinin 3 receptor increases Nav1.9 current in enteric neurons. J. Physiol. 587, 1461–1479 (2009).

  33. 33

    Osorio, N., Korogod, S. & Delmas, P. Specialized functions of Nav1.5 and Nav1.9 channels in electrogenesis of myenteric neurons in intact mouse ganglia. J. Neurosci. 34, 5233–5244 (2014).

  34. 34

    Dib-Hajj, S. D., Cummins, T. R., Black, J. A. & Waxman, S. G. Sodium channels in normal and pathological pain. Annu. Rev. Neurosci. 33, 325–347 (2010).

  35. 35

    Qiu, F., Jiang, Y., Zhang, H., Liu, Y. & Mi, W. Increased expression of tetrodotoxin-resistant sodium channels Nav1.8 and Nav1.9 within dorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett. 512, 61–66 (2012).

  36. 36

    Petho, G. & Reeh, P. W. Sensory and signaling mechanisms of bradykinin, eicosanoids, platelet-activating factor, and nitric oxide in peripheral nociceptors. Physiol. Rev. 92, 1699–1775 (2012).

  37. 37

    Rush, A. M. & Waxman, S. G. PGE2 increases the tetrodotoxin-resistant Nav1.9 sodium current in mouse DRG neurons via G-proteins. Brain Res. 1023, 264–271 (2004).

  38. 38

    Binshtok, A. M. et al. Nociceptors are interleukin-1β sensors. J. Neurosci. 28, 14062–14073 (2008).

  39. 39

    Maingret, F. et al. Inflammatory mediators increase Nav1.9 current and excitability in nociceptors through a coincident detection mechanism. J. Gen. Physiol. 131, 211–225 (2008).

  40. 40

    Mogil, J. S. Animal models of pain: progress and challenges. Nat. Rev. Neurosci. 10, 283–294 (2009).

  41. 41

    Dib-Hajj, S. D. & Waxman, S. G. Translational pain research: lessons from genetics and genomics. Sci. Transl Med. 6, 249sr244 (2014).

  42. 42

    Black, J. A. & Waxman, S. G. Molecular identities of two tetrodotoxin-resistant sodium channels in corneal axons. Exp. Eye Res. 75, 193–199 (2002).

  43. 43

    Padilla, F. 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. 35, 138–152 (2007).

  44. 44

    Belmonte, C. & Gallar, J. Cold thermoreceptors, unexpected players in tear production and ocular dryness sensations. Invest. Ophthalmol. Vis. Sci. 52, 3888–3892 (2011).

  45. 45

    Rosenthal, P. & Borsook, D. The corneal pain system. Part I: the missing piece of the dry eye puzzle. Ocul. Surf. 10, 2–14 (2012).

  46. 46

    Dib-Hajj, S. D. et al. Transfection of rat or mouse neurons by biolistics or electroporation. Nat. Protoc. 4, 1118–1126 (2009).

  47. 47

    Waxman, S. G. et al. Sodium channel genes in pain-related disorders: phenotype–genotype associations and recommendations for clinical use. Lancet Neurol. 13, 1152–1160 (2014).

  48. 48

    Faber, C. G. et al. Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy. Ann. Neurol. 71, 26–39 (2012).

  49. 49

    Han, C. et al. Functional profiles of SCN9A variants in dorsal root ganglion neurons and superior cervical ganglion neurons correlate with autonomic symptoms in small fibre neuropathy. Brain 135, 2613–2628 (2012).

  50. 50

    Rush, A. M. et al. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl Acad. Sci. USA 103, 8245–8250 (2006).

  51. 51

    Shields, S. D. et al. NaV1.8 expression is not restricted to nociceptors in mouse peripheral nervous system. Pain 153, 2017–2030 (2012).

  52. 52

    Waxman, S. G., Black, J. A., Kocsis, J. D. & Ritchie, J. M. Low density of sodium channels supports action potential conduction in axons of neonatal rat optic nerve. Proc. Natl Acad. Sci. USA 86, 1406–1410 (1989).

  53. 53

    Donnelly, D. F. Spontaneous action potential generation due to persistent sodium channel currents in simulated carotid body afferent fibers. J. Appl. Physiol. 104, 1394–1401 (2008).

  54. 54

    Stys, P. K., Waxman, S. G. & Ransom, B. R. Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na+–Ca2+ exchanger. J. Neurosci. 12, 430–439 (1992).

  55. 55

    Persson, A. K. et al. Neuropathy-associated NaV1.7 variant I228M impairs integrity of dorsal root ganglion neuron axons. Ann. Neurol. 73, 140–145 (2012).

  56. 56

    Swadlow, H. A. & Waxman, S. G. Observations on impulse conduction along central axons. Proc. Natl Acad. Sci. USA 72, 5156–5159 (1975).

  57. 57

    Chambers, S. M. et al. Combined small-molecule inhibition accelerates developmental timing and converts human pluripotent stem cells into nociceptors. Nat. Biotechnol. 30, 715–720 (2012).

  58. 58

    Young, G. T. et al. Characterizing human stem cell-derived sensory neurons at the single-cell level reveals their ion channel expression and utility in pain research. Mol. Ther. 22, 1530–1543 (2014).

  59. 59

    Blanchard, J. W. et al. Selective conversion of fibroblasts into peripheral sensory neurons. Nat. Neurosci. 18, 25–35 (2015).

  60. 60

    Wainger, B. J. et al. Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts. Nat. Neurosci. 18, 17–24 (2015).

  61. 61

    Baker, M. Gene editing at CRISPR speed. Nat. Biotechnol. 32, 309–312 (2014).

  62. 62

    McCormack, K. et al. Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels. Proc. Natl Acad. Sci. USA 110, E2724–E2732 (2013).

  63. 63

    Lee, J. H. et al. A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief. Cell 157, 1393–1404 (2014).

  64. 64

    Black, J. A., Vasylyev, D., Dib-Hajj, S. D. & Waxman, S. G. Nav1.9 expression inmagnocellular neurosecretory cells of supraoptic nucleus. Exp. Neurol. 253, 174–179 (2014).

  65. 65

    Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009).

  66. 66

    Woolf, C. J. & Ma, Q. Nociceptors — noxious stimulus detectors. Neuron 55, 353–364 (2007).

Download references


The authors thank the members of their group for valuable discussions. Work in the authors' laboratory is supported in part by grants from the US Rehabilitation Research and Development Service and Medical Research Service, the US Department of Veterans Affairs and the Erythromelalgia Association. The Center for Neuroscience and Regeneration Research is a collaboration of the Paralyzed Veterans of America with Yale University, New Haven, Connecticut, USA.

Author information

Correspondence to Stephen G. Waxman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dib-Hajj, S., Black, J. & Waxman, S. NaV1.9: a sodium channel linked to human pain. Nat Rev Neurosci 16, 511–519 (2015) doi:10.1038/nrn3977

Download citation

Further reading