Skip to main content

Thank you for visiting 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.

  • Letter
  • Published:

Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures


Sensory acuity and motor dexterity deteriorate when human limbs cool down, but pain perception persists and cold-induced pain can become excruciating1. Evolutionary pressure to enforce protective behaviour requires that damage-sensing neurons (nociceptors) continue to function at low temperatures. Here we show that this goal is achieved by endowing superficial endings of slowly conducting nociceptive fibres with the tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Nav1.8 (ref. 2). This channel is essential for sustained excitability of nociceptors when the skin is cooled. We show that cooling excitable membranes progressively enhances the voltage-dependent slow inactivation of tetrodotoxin-sensitive VGSCs. In contrast, the inactivation properties of Nav1.8 are entirely cold-resistant. Moreover, low temperatures decrease the activation threshold of the sodium currents and increase the membrane resistance, augmenting the voltage change caused by any membrane current. Thus, in the cold, Nav1.8 remains available as the sole electrical impulse generator in nociceptors that transmits nociceptive information to the central nervous system. Consistent with this concept is the observation that Nav1.8-null mutant mice3 show negligible responses to noxious cold and mechanical stimulation at low temperatures. Our data present strong evidence for a specialized role of Nav1.8 in nociceptors as the critical molecule for the perception of cold pain and pain in the cold.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: TTX-blocked sensory C-fibre terminals regain responsiveness on cooling.
Figure 2: Low temperature differentially affects TTXs and TTXr VGSCs.
Figure 3: Loss of Na v 1.8 impairs responsiveness to noxious stimulation in the cold.
Figure 4: Cooling increases TTXr excitability in nociceptive terminals.

Similar content being viewed by others


  1. Solomon, S. & Stearns, C. R. On the role of the weather in the deaths of R. F. Scott and his companions. Proc. Natl Acad. Sci. USA 96, 13012–13016 (1999)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Peier, A. M. et al. A TRP channel that senses cold stimuli and menthol. Cell 108, 705–715 (2002)

    Article  CAS  Google Scholar 

  5. McKemy, D. D., Neuhausser, W. M. & Julius, D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416, 52–58 (2002)

    Article  ADS  CAS  Google Scholar 

  6. Kwan, K. Y. et al. TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron 50, 277–289 (2006)

    Article  CAS  Google Scholar 

  7. Story, G. M. et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819–829 (2003)

    Article  CAS  Google Scholar 

  8. Babes, A., Zorzon, D. & Reid, G. Two populations of cold-sensitive neurons in rat dorsal root ganglia and their modulation by nerve growth factor. Eur. J. Neurosci. 20, 2276–2282 (2004)

    Article  Google Scholar 

  9. Brock, J. A., McLachlan, E. M. & Belmonte, C. Tetrodotoxin-resistant impulses in single nociceptor nerve terminals in guinea-pig cornea. J. Physiol. (Lond.) 512, 211–217 (1998)

    Article  CAS  Google Scholar 

  10. 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)

    Article  CAS  Google Scholar 

  11. 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)

    Article  CAS  Google Scholar 

  12. Strassman, A. M. & Raymond, S. A. Electrophysiological evidence for tetrodotoxin-resistant sodium channels in slowly conducting dural sensory fibers. J. Neurophysiol. 81, 413–424 (1999)

    Article  CAS  Google Scholar 

  13. 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)

    Article  CAS  Google Scholar 

  14. Reeh, P. W. Sensory receptors in mammalian skin in an in vitro preparation. Neurosci. Lett. 66, 141–146 (1986)

    Article  CAS  Google Scholar 

  15. Wood, J. N., Boorman, J. P., Okuse, K. & Baker, M. D. Voltage-gated sodium channels and pain pathways. J. Neurobiol. 61, 55–71 (2004)

    Article  CAS  Google Scholar 

  16. Matsutomi, T., Nakamoto, C., Zheng, T., Kakimura, J. & Ogata, N. Multiple types of Na+ currents mediate action potential electrogenesis in small neurons of mouse dorsal root ganglia. Pflügers Arch. 453, 83–96 (2006)

    Article  CAS  Google Scholar 

  17. Renganathan, M., Cummins, T. R. & Waxman, S. G. Contribution of Nav1.8 sodium channels to action potential electrogenesis in DRG neurons. J. Neurophysiol. 86, 629–640 (2001)

    Article  CAS  Google Scholar 

  18. Bautista, D. M. et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124, 1269–1282 (2006)

    Article  CAS  Google Scholar 

  19. Bostock, H. The strength–duration relationship for excitation of myelinated nerve: computed dependence on membrane parameters. J. Physiol. (Lond.) 341, 59–74 (1983)

    Article  CAS  Google Scholar 

  20. Hodkin, A. L. & Katz, B. The effect of temperature on the electrical activity of the giant axon of the squid. J. Physiol. (Lond.) 109, 240–249 (1949)

    Article  Google Scholar 

  21. Thompson, S. M., Masukawa, L. M. & Prince, D. A. Temperature dependence of intrinsic membrane properties and synaptic potentials in hippocampal CA1 neurons in vitro. J. Neurosci. 5, 817–824 (1985)

    Article  CAS  Google Scholar 

  22. Volgushev, M., Vidyasagar, T. R., Chistiakova, M., Yousef, T. & Eysel, U. T. Membrane properties and spike generation in rat visual cortical cells during reversible cooling. J. Physiol. (Lond.) 522, 59–76 (2000)

    Article  CAS  Google Scholar 

  23. Reid, G. & Flonta, M. Cold transduction by inhibition of a background potassium conductance in rat primary sensory neurones. Neurosci. Lett. 297, 171–174 (2001)

    Article  CAS  Google Scholar 

  24. Viana, F., de la Pena, E. & Belmonte, C. Specificity of cold thermotransduction is determined by differential ionic channel expression. Nature Neurosci. 5, 254–260 (2002)

    Article  CAS  Google Scholar 

  25. Pierau, F. K., Torrey, P. & Carpenter, D. O. Mammalian cold receptor afferents: role of an electrogenic sodium pump in sensory transduction. Brain Res. 73, 156–160 (1974)

    Article  CAS  Google Scholar 

  26. Goldin, A. L. Evolution of voltage-gated Na+ channels. J. Exp. Biol. 205, 575–584 (2002)

    CAS  PubMed  Google Scholar 

  27. Matthews, E. A., Wood, J. N. & Dickenson, A. H. Nav 1.8-null mice show stimulus-dependent deficits in spinal neuronal activity. Mol. Pain 2, 5 (2006)

    Article  Google Scholar 

  28. 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)

    Article  ADS  CAS  Google Scholar 

  29. Leffler, A., Reiprich, A., Mohapatra, D. P. & Nau, C. 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 (2007)

    Article  CAS  Google Scholar 

  30. Dittert, I. et al. Improved superfusion technique for rapid cooling or heating of cultured cells under patch-clamp conditions. J. Neurosci. Methods 151, 178–185 (2006)

    Article  Google Scholar 

Download references


We thank H. Bostock and O. Krishtal for discussions. This work was supported by the Wellcome Trust, the MRC, SEUI/MEC, the German Research Foundation and the Humboldt Foundation.

Author Contributions J.K. made the decisive discovery that TTX-blocked rat CMC fibres fired in response to noxious cold stimulation. A.L. performed the voltage-clamp recordings, A.B. the current-clamp recordings, and K.Z. and P.W.R. the skin-nerve recordings. J.N.W. and C.M.C. provided the mice and conducted behavioural experiments. C.N. provided heterologously expressed Nav1.7 and Nav1.8. R.W.C. wrote a script for Spike2 enabling the modified excitability testing.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Katharina Zimmermann.

Ethics declarations

Competing interests

Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Information 1

This file contains Supplementary Notes, Supplementary Figures S1-S7 and additional references. (PDF 5842 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zimmermann, K., Leffler, A., Babes, A. et al. Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature 447, 856–859 (2007).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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