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A novel role for TRPM8 in visceral afferent function

Harrington, Andrea M.a,b,*; Hughes, Patrick A.a,b; Martin, Christopher M.a; Yang, Jinga,b; Castro, Joela; Isaacs, Nicole J.a; Blackshaw, Ashley L.a,b,c; Brierley, Stuart M.a,b,c

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doi: 10.1016/j.pain.2011.01.027
Research papers
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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.

TRPM8 was localised to high-threshold visceral afferent neurons. On visceral afferent peripheral endings, TRPM8 activation affected TRPV1 and TRPA1 downstream chemosensory and mechanosensory actions.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

aNerve-Gut Research Laboratory, Department of Gastroenterology & Hepatology, Hanson Institute, Royal Adelaide Hospital, Adelaide, South Australia, Australia

bDiscipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia

cDiscipline of Physiology, University of Adelaide, Adelaide, South Australia, Australia

*Corresponding author at: Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia. Tel.: +61 8 8222 2602; fax: +61 8 8222 5934.

E-mail address:andrea.harrington@health.sa.gov.au

Article history: Received 15 July 2010; Received in revised form 24 November 2010; Accepted 14 January 2011.

© 2011 Lippincott Williams & Wilkins, Inc.
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