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

Katharina Zimmermann*, Andreas Leffler, Alexandru Babes, Cruz Miguel Cendan, Richard W. Carr, Jin Ichi Kobayashi, Carla Nau, John N. Wood, Peter W. Reeh

*Corresponding author for this work
289 Citations (Scopus)


Sensory acuity and motor dexterity deteriorate when human limbs cool down, but pain perception persists and cold-induced pain can become excruciating. 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 mice 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.

Original languageEnglish
Issue number7146
Pages (from-to)855-858
Number of pages4
Publication statusPublished - 14.06.2007


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