1. Department of Physiology and Pathophysiology,
2. Department of Anesthesiology, Faculty of Medicine, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany
3. Department of Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania
4. Department of Biology, University College London, London WC1E 6BT, UK
5. Department of Fixed Prosthodontics, Faculty of Dental Science, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan
6. These authors contributed equally to this work.

Correspondence to: Katharina Zimmermann^1,6 Correspondence and requests for materials should be addressed to K.Z. (Email: zimmermann@physiologie1.uni-erlangen.de).

Abstract

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) Na_v1.8 (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 Na_v1.8 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, Na_v1.8 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 Na_v1.8-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 Na_v1.8 in nociceptors as the critical molecule for the perception of cold pain and pain in the cold.

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