Topically applied camphor elicits a sensation of cool, but nothing is known about how it affects cold temperature sensing. We found that camphor sensitizes a subpopulation of menthol-sensitive native cutaneous nociceptors in the mouse to cold, but desensitizes and partially blocks heterologously expressed TRPM8 (transient receptor potential cation channel subfamily M member 8). In contrast, camphor reduces potassium outward currents in cultured sensory neurons and, in cold nociceptors, the cold-sensitizing effects of camphor and menthol are additive. Using a membrane potential dye-based screening assay and heterologously expressed potassium channels, we found that the effects of camphor are mediated by inhibition of Kv7.2/3 channels subtypes that generate the M-current in neurons. In line with this finding, the specific M-current blocker XE991 reproduced the cold-sensitizing effect of camphor in nociceptors. However, the M-channel blocking effects of XE991 and camphor are not sufficient to initiate cold transduction but require a cold-activated inward current generated by TRPM8. The cold-sensitizing effects of XE991 and camphor are largest in high-threshold cold nociceptors. Low-threshold corneal cold thermoreceptors that express high levels of TRPM8 and lack potassium channels are not affected by camphor. We also found that menthol--like camphor--potently inhibits Kv7.2/3 channels. The apparent functional synergism arising from TRPM8 activation and M-current block can improve the effectiveness of topical coolants and cooling lotions, and may also enhance TRPM8-mediated analgesia.

Institute for Molecular Bioscience The University of Queensland St Lucia 4072 Queensland Australia Department of Physiology and Pathophysiology Friedrich Alexander Universität Erlangen Nürnberg 91054 Erlangen Germany Department of Cellular Neurophysiology Institute of Physiology Academy of Sciences of the Czech Republic CZ 14220 Prague Czech Republic Instituto de Neurociencias de Alicante Universidad Miguel Hernandez Consejo Superior de Investigaciones Cientificas 03550 San Juan de Alicante Spain Department of Anesthesiology and Intensive Care Medical School Hannover 30625 Hannover Germany and Department of Gynecology and Obstetrics Friedrich Alexander Universität Erlangen Nürnberg 91054 Erlangen Germany

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