A novel role for TRPM8 in visceral afferent function

Pain. 2011 Jul;152(7):1459-68. doi: 10.1016/j.pain.2011.01.027. Epub 2011 Apr 13.

Abstract

Transient receptor potential ion channel melastatin subtype 8 (TRPM8) is activated by cold temperatures and cooling agents, such as menthol and icilin. Compounds containing peppermint are reported to reduce symptoms of bowel hypersensitivity; however, the underlying mechanisms of action are unclear. Here we determined the role of TRPM8 in colonic sensory pathways. Laser capture microdissection, quantitative reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence, and retrograde tracing were used to localise TRPM8 to colonic primary afferent neurons. In vitro extracellular single-fibre afferent recordings were used to determine the effect of TRPM8 channel activation on the chemosensory and mechanosensory function of colonic high-threshold afferent fibres. TRPM8 mRNA was present in colonic DRG neurons, whereas TRPM8 protein was present on nerve fibres throughout the wall of the colon. A subpopulation (24%, n=58) of splanchnic serosal and mesenteric afferents tested responded directly to icilin (5 μmol/L). Subsequently, icilin significantly desensitised afferents to mechanical stimulation (P<.0001; n=37). Of the splanchnic afferents responding to icilin, 21 (33%) also responded directly to the TRPV1 agonist capsaicin (3 μmol/L), and icilin reduced the direct chemosensory response to capsaicin. Icilin also prevented mechanosensory desensitization and sensitization induced by capsaicin and the TRPA1 agonist AITC (40 μmol/L), respectively. TRPM8 is present on a select population of colonic high threshold sensory neurons, which may also co-express TRPV1. TRPM8 couples to TRPV1 and TRPA1 to inhibit their downstream chemosensory and mechanosensory actions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Calcitonin Gene-Related Peptide / metabolism
  • Cells, Cultured
  • Cholera Toxin / metabolism
  • Colon / innervation
  • Fluorescent Dyes / metabolism
  • Ganglia, Spinal / cytology
  • Gene Expression / drug effects
  • Gene Expression / physiology*
  • Hyperalgesia / genetics
  • Hyperalgesia / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microdissection / methods
  • Pyrimidinones / pharmacology
  • Sensory Receptor Cells / metabolism
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism*
  • TRPV Cation Channels / deficiency
  • TRPV Cation Channels / metabolism
  • Visceral Afferents / cytology
  • Visceral Afferents / drug effects
  • Visceral Afferents / metabolism*

Substances

  • Fluorescent Dyes
  • Pyrimidinones
  • TRPM Cation Channels
  • TRPM8 protein, mouse
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Cholera Toxin
  • icilin
  • Calcitonin Gene-Related Peptide