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.
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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)
Akopian, A. N., Sivilotti, L. & Wood, J. N. A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379, 257–262 (1996)
Akopian, A. N. et al. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nature Neurosci. 2, 541–548 (1999)
Peier, A. M. et al. A TRP channel that senses cold stimuli and menthol. Cell 108, 705–715 (2002)
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)
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)
Story, G. M. et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819–829 (2003)
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)
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)
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)
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)
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)
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)
Reeh, P. W. Sensory receptors in mammalian skin in an in vitro preparation. Neurosci. Lett. 66, 141–146 (1986)
Wood, J. N., Boorman, J. P., Okuse, K. & Baker, M. D. Voltage-gated sodium channels and pain pathways. J. Neurobiol. 61, 55–71 (2004)
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)
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)
Bautista, D. M. et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124, 1269–1282 (2006)
Bostock, H. The strength–duration relationship for excitation of myelinated nerve: computed dependence on membrane parameters. J. Physiol. (Lond.) 341, 59–74 (1983)
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)
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)
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)
Reid, G. & Flonta, M. Cold transduction by inhibition of a background potassium conductance in rat primary sensory neurones. Neurosci. Lett. 297, 171–174 (2001)
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)
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)
Goldin, A. L. Evolution of voltage-gated Na+ channels. J. Exp. Biol. 205, 575–584 (2002)
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)
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)
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)
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)
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.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
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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). https://doi.org/10.1038/nature05880
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