title: Camphor activates and sensitizes transient receptor potential melastatin 8 (TRPM8) to cooling and icilin.
abstract: Camphor is known to potentiate both heat and cold sensations. Although the sensitization to heat could be explained by the activation of heat-sensitive transient receptor potential (TRP) channels TRPV1 and TRPV3, the camphor-induced sensitization to cooling remains unexplained. In this study, we present evidence for the activation of the cold- and menthol-sensitive channel transient receptor potential melastatin 8 (TRPM8) by camphor. Calcium transients evoked by camphor in HEK293 cells expressing human and rat TRPM8 are inhibited by the TRPM8 antagonists 4-(3-chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)phenyl]-1-piperazinecarboxamide and 2-aminoethyl diphenylborinate. Camphor also sensitized the cold-induced calcium transients and evoked desensitizing outward-rectifying currents in TRPM8-expressing HEK293 cells. In the presence of ruthenium red (a blocker of TRPV1, TRPV3, and TRPA1), the camphor sensitivity of cultured rat dorsal root ganglion neurons was highest in a subpopulation of cold- and icilin-sensitive neurons, strongly suggesting that camphor activates native TRPM8. Camphor has a dual action on TRPM8: it not only activates the channel but also inhibits its response to menthol. The icilin-insensitive chicken TRPM8 was also camphor insensitive. However, camphor was able to activate an icilin-insensitive human TRPM8 mutant channel. The activation and sensitization to cold of mammalian TRPM8 are likely to be responsible for the psychophysical enhancement of innocuous cold and "stinging/burning" cold sensations by camphor.
authors.affiliation: Department of Anatomy, Physiology and Biophysics, Faculty of Biology, University of Bucharest, Splaiul Independentei 91-95, 050095 Bucharest, Romania. tudorselescu@yahoo.com
authors.forename: Tudor
authors.initials: T
authors.lastname: Selescu
authors.forename: Alexandru C
authors.initials: AC
authors.lastname: Ciobanu
authors.forename: Cristian
authors.initials: C
authors.lastname: Dobre
authors.forename: Gordon
authors.initials: G
authors.lastname: Reid
authors.forename: Alexandru
authors.initials: A
authors.lastname: Babes
mesh_terms: D000818:Animals; D001483:Base Sequence; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002164:Camphor / Q000819:agonists / Q000494:pharmacology*; D002478:Cells, Cultured; D002645:Chickens / Q000235:genetics; D003080:Cold Temperature; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology / Q000379:methods; D005727:Ganglia, Spinal / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008610:Menthol / Q000494:pharmacology; D008969:Molecular Sequence Data; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012430:Ruthenium Red / Q000494:pharmacology; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: C538758:2-aminoethyl diphenylborinate; D001896:Boron Compounds; D011744:Pyrimidinones; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; C498947:Trpm8 protein, rat; D012430:Ruthenium Red; D008610:Menthol; D002164:Camphor; C490483:icilin; D002118:Calcium
keywords: chicken TRPM8; dorsal root ganglion; eucalyptol; human TRPM8; icilin; menthol