Topical application of TRPM8 agonists accelerates skin permeability barrier recovery and reduces epidermal proliferation induced by barrier insult: role of cold-sensitive TRP receptors in epidermal permeability barrier homoeostasis

Exp Dermatol. 2010 Sep;19(9):791-5. doi: 10.1111/j.1600-0625.2010.01154.x. Epub 2010 Jul 16.


TRPA1 and TRPM8 receptors are activated at low temperature (A1: below 17 degrees C and M8: below 22 degrees C). Recently, we observed that low temperature (below 22 degrees C) induced elevation of intracellular calcium in keratinocytes. Moreover, we demonstrated that topical application of TRPA1 agonists accelerated the recovery of epidermal permeability barrier function after disruption. In this study, we examined the effect of topical application of TRPM8 modulators on epidermal permeability barrier homoeostasis. Immunohistochemical study and RT-PCR confirmed the expression of TRPM8 or TRPM8-like protein in epidermal keratinocytes. Topical application of TRPM8 agonists, menthol and WS 12 accelerated barrier recovery after tape stripping. The effect of WS12 was blocked by a non-selective TRP antagonist, Ruthenium Red, and a TRPM8-specific antagonist, BTCT. Topical application of WS12 also reduced epidermal proliferation associated with barrier disruption under low humidity, and this effect was blocked by BTCT. Our results indicate that TRPM8 or a closely related protein in epidermal keratinocytes plays a role in epidermal permeability barrier homoeostasis and epidermal proliferation after barrier insult.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Cutaneous
  • Anilides / administration & dosage
  • Animals
  • Cells, Cultured
  • Epidermis / metabolism*
  • Epidermis / pathology
  • Homeostasis
  • Humans
  • Hyperplasia / drug therapy
  • Keratinocytes / metabolism*
  • Male
  • Menthol / administration & dosage
  • Menthol / analogs & derivatives
  • Mice
  • Mice, Hairless
  • Permeability
  • Pyrazines / administration & dosage
  • Pyridines / administration & dosage
  • Ruthenium Red / administration & dosage
  • Skin Diseases / drug therapy
  • Skin Diseases / pathology
  • TRPM Cation Channels / agonists
  • TRPM Cation Channels / antagonists & inhibitors
  • TRPM Cation Channels / metabolism*


  • Anilides
  • N-(4-methoxyphenyl)-4-menthone-3-carboxamide
  • N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide
  • Pyrazines
  • Pyridines
  • TRPM Cation Channels
  • TRPM8 protein, mouse
  • Ruthenium Red
  • Menthol