title: Amplified cold transduction in native nociceptors by M-channel inhibition.
abstract: 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.
authors.affiliation: 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.
authors.forename: Irina
authors.initials: I
authors.lastname: Vetter
authors.forename: Alexander
authors.initials: A
authors.lastname: Hein
authors.forename: Simon
authors.initials: S
authors.lastname: Sattler
authors.forename: Sabine
authors.initials: S
authors.lastname: Hessler
authors.forename: Filip
authors.initials: F
authors.lastname: Touska
authors.forename: Elisangela
authors.initials: E
authors.lastname: Bressan
authors.forename: Andres
authors.initials: A
authors.lastname: Parra
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hager
authors.forename: Andreas
authors.initials: A
authors.lastname: Leffler
authors.forename: Stepana
authors.initials: S
authors.lastname: Boukalova
authors.forename: Matthias
authors.initials: M
authors.lastname: Nissen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.forename: Carlos
authors.initials: C
authors.lastname: Belmonte
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
authors.forename: Tobias
authors.initials: T
authors.lastname: Huth
authors.forename: Viktorie
authors.initials: V
authors.lastname: Vlachova
authors.forename: Peter W
authors.initials: PW
authors.lastname: Reeh
authors.forename: Katharina
authors.initials: K
authors.lastname: Zimmermann
mesh_terms: D000818:Animals; D002164:Camphor / Q000494:pharmacology; D003080:Cold Temperature; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008610:Menthol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D013823:Thermoreceptors / Q000378:metabolism / Q000502:physiology*; D013697:Thermosensing / Q000187:drug effects / Q000502:physiology*
chemical_list: D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D008610:Menthol; D002164:Camphor