• Irina Vetter, Alexander Hein, Simon Sattler, Sabine Hessler, Filip Touska, Elisangela Bressan, Andres Parra, Ulrich Hager, Andreas Leffler, Stepana Boukalova, Matthias Nissen, Richard J Lewis, Carlos Belmonte, Christian Alzheimer, Tobias Huth, Viktorie Vlachova, Peter W Reeh, and Katharina Zimmermann.
• 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.
• J. Neurosci. 2013 Oct 16; 33 (42): 16627-41.

AbstractTopically 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.

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