title: Menthol activation of corneal cool cells induces TRPM8-mediated lacrimation but not nociceptive responses in rodents.
abstract: OBJECTIVE
  Stimulation to the cornea via noxious chemical and mechanical means evokes tearing, blinking, and pain. In contrast, mild cooling of the ocular surface has been reported to increase lacrimation via activation of corneal cool primary afferent neurons. The purpose of our study was to determine whether menthol induces corneal cool cell activity and lacrimation via the transient receptor potential melastatin-8 (TRPM8) channel without evoking nociceptive responses.
  
  
  METHODS
  Tear measurements were made using a cotton thread in TRPM8 wild type and knockout mice after application of menthol (0.05-50 mM) to the cornea. In additional studies, nocifensive responses (eye swiping and lid closure) were quantified following cornea menthol application. Trigeminal ganglion electrophysiologic single unit recordings were performed in rats to determine the effect of low and high concentrations of menthol on corneal cool cells.
  
  
  RESULTS
  At low concentrations, menthol increased tear production in TRPM8 wild type and heterozygous animals, but had no effect in TRPM8 knockout mice, while nocifensive responses remained unaffected. At the highest concentration, menthol (50 mM) increased tearing and nocifensive responses in TRPM8 wild type and knockout animals. A low concentration of menthol (0.1 mM) increased cool cell activity, yet a high concentration of menthol (50 mM) had no effect.
  
  
  CONCLUSIONS
  These studies indicated that low concentrations of menthol can increase lacrimation via TRPM8 channels without evoking nocifensive behaviors. At high concentrations, menthol can induce lacrimation and nocifensive behaviors in a TRPM8 independent mechanism. The increase in lacrimation is likely due to an increase in cool cell activity.
authors.affiliation: Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, Maine 04005, USA.
authors.forename: Ashlee
authors.initials: A
authors.lastname: Robbins
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kurose
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Winterson
authors.forename: Ian D
authors.initials: ID
authors.lastname: Meng
mesh_terms: D000818:Animals; D001767:Blinking / Q000187:drug effects; D003315:Cornea / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D004594:Electrophysiology; D015590:Fluorophotometry; D007765:Lacrimal Apparatus / Q000378:metabolism; D008297:Male; D000432:Methanol / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009475:Neurons, Afferent / Q000502:physiology; D059225:Nociception / Q000502:physiology*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D050053:TRPM Cation Channels / Q000378:metabolism*; D013666:Tears / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000502:physiology
chemical_list: D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D000432:Methanol