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.

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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.


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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.

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Correspondence to Katharina Zimmermann.

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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).

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