title: 1,8-cineole, a TRPM8 agonist, is a novel natural antagonist of human TRPA1.
abstract: BACKGROUND
  Essential oils are often used in alternative medicine as analgesic and anti-inflammatory remedies. However, the specific compounds that confer the effects of essential oils and the molecular mechanisms are largely unknown. TRPM8 is a thermosensitive receptor that detects cool temperatures and menthol whereas TRPA1 is a sensor of noxious cold. Ideally, an effective analgesic compound would activate TRPM8 and inhibit TRPA1.
  
  
  RESULTS
  We screened essential oils and fragrance chemicals showing a high ratio of human TRPM8-activating ability versus human TRPA1-activating ability using a Ca2+-imaging method, and identified 1,8-cineole in eucalyptus oil as particularly effective. Patch-clamp experiments confirmed that 1,8-cineole evoked inward currents in HEK293T cells expressing human TRPM8, but not human TRPA1. In addition, 1,8-cineole inhibited human TRPA1 currents activated by allyl isothiocyanate, menthol, fulfenamic acid or octanol in a dose-dependent manner. Furthermore, in vivo sensory irritation tests showed that 1,8-cineole conferred an analgesic effect on sensory irritation produced by TRPA1 agonists octanol and menthol. Surprisingly, 1,4-cineole, which is structurally similar and also present in eucalyptus oil, activated both human TRPM8 and human TRPA1.
  
  
  CONCLUSIONS
  1,8-cineole is a rare natural antagonist of human TRPA1 that has analgesic and anti-inflammatory effects possibly due to its inhibition of TRPA1.
authors.affiliation: Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takaishi
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Fujita
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Uchida
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Maki
authors.initials: M
authors.lastname: Sawada Shimizu
authors.forename: Chihiro
authors.initials: C
authors.lastname: Hatai Uotsu
authors.forename: Mayumi
authors.initials: M
authors.lastname: Shimizu
authors.forename: Makoto
authors.initials: M
authors.lastname: Tominaga
mesh_terms: D015220:Calcium Channels; D002460:Cell Line; D000081005:Cyclohexane Monoterpenes; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology; D008610:Menthol / Q000494:pharmacology; D039821:Monoterpenes / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D000442:Octanols / Q000494:pharmacology; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels / Q000819:agonists*; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors*
chemical_list: D015220:Calcium Channels; D000081005:Cyclohexane Monoterpenes; D017879:Isothiocyanates; D039821:Monoterpenes; D009419:Nerve Tissue Proteins; D000442:Octanols; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D050051:Transient Receptor Potential Channels; D008610:Menthol; C058951:1,4-cineole; C004471:allyl isothiocyanate