TRPM8 has a key role in experimental colitis-induced visceral hyperalgesia in mice.
BACKGROUND
Transient receptor potential channel melastatin 8 (TRPM8) is activated by cold temperatures and cooling agents (menthol and icilin). Recent studies showed TRPM8 is expressed in visceral organs and peripheral sensory pathways. However, the role of TRPM8 in visceral hyperalgesia is poorly understood in pathological states such as inflammatory bowel disease. Hence, we investigated the distribution of TRPM8 and its involvement in visceral hyperalgesia in experimental colitis mice.


METHODS
TRPM8 immunoreactivity was detected using immunohistochemical staining with fluorescein-conjugated tyramide amplification. Visceral hyperalgesia was measured by the intracolonic administration of TRPM8 agonist, WS-12, in control and dextran sodium sulfate (DSS)-induced colitis mice.


RESULTS
TRPM8 immunoreactivity in the distal colon was much higher than in the transverse and proximal colon under physiological conditions. TRPM8 immunoreactivity markedly increased in the distal colon mucosa of DSS-induced colitis mice compared with control mice. The number of TRPM8 nerve fibers in mucosa of DSS- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis model mice drastically increased compared with control mice. TRPM8 immunoreactivities colocalized with the calcitonin gene-related peptide- and substance P-immunoreactive nerve fibers in the mucosa. Intracolonic administration of WS-12 induced behavioral visceral pain-like responses. The numbers of these responses in the colitis model mice were 3 times higher than in control mice, and were decreased by pretreatment with the TRPM8 channel blocker AMTB.


CONCLUSIONS
Increased expression of TRPM8 may contribute to the visceral hyperalgesia of experimental colitis.
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, Togane, Japan; Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
T
T
Hosoya
K
K
Matsumoto
K
K
Tashima
H
H
Nakamura
H
H
Fujino
T
T
Murayama
S
S
Horie
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000150:complications*; D003106:Colon / Q000378:metabolism*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism* / Q000523:psychology; D008297:Male; D008610:Menthol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009412:Nerve Fibers / Q000378:metabolism; D050053:TRPM Cation Channels / Q000819:agonists / Q000378:metabolism*
D000813:Anilides; C533807:N-(4-methoxyphenyl)-4-menthone-3-carboxamide; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D008610:Menthol; D016264:Dextran Sulfate
TRPM8; colitis; immunohistochemistry; visceral hyperalgesia