Role of transient receptor potential melastatin 2 (TRPM2) channels in visceral nociception and hypersensitivity.
Transient receptor potential melastatin 2 (TRPM2) is a thermosensitive, Ca2+-permeable cation channel. TRPM2 contributes to the pathogenesis of inflammatory bowel disease, and inflammatory and neuropathic pain. We hypothesized that TRPM2 is important for visceral nociception and the development of visceral hypersensitivity. Therefore, we investigated the expression of TRPM2 channels and their involvement in visceral nociception in normal physiology and under pathological conditions that cause visceral hypersensitivity in rats. TRPM2 immunoreactivities were detected in the mucosa and muscle layer of the rat gastrointestinal tract. TRPM2 immunopositive cell bodies were almost completely co-localized with calretinin- and NeuN-positive cells in the myenteric plexus. We found that the majority of the TRPM2-immunoreactive cells were double-labeled with the retrograde marker fluorogold in lumbar 6/sacral 1 dorsal root ganglia (DRG), indicating that TRPM2 is expressed in spinal primary afferents innervating the distal colon. Subtypes of TRPM2-immunopositive DRG neurons were labeled by the A-fiber marker NF200, the C-fiber marker IB4, substance P, calcitonin gene-related peptide, or P2X3 receptor. We found that oral administration of the TRPM2 inhibitor econazole (30mg/kg) reduced the visceromotor response (VMR) to noxious colorectal distention (CRD) at 80mmHg in control rats. Expression of TRPM2 in the mucosa of the distal colon was increased in a trinitrobenzene sulfonic acid-induced colitis model. The VMR to CRD significantly increased in colitis model rats compared with control rats at 40, 60, and 80mmHg. Econazole restored visceral hypersensitivity to the control level. Furthermore, TRPM2-deficient mice showed significantly attenuated trinitrobenzene sulfonic acid induced visceral hypersensitivity compared with wild-type mice. In conclusion, TRPM2 channels contribute to visceral nociception in response to noxious stimuli under normal conditions and visceral hypersensitivity in pathological conditions.
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, Togane, Japan; Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Japan. Electronic address: kenjiro@mb.kyoto-phu.ac.jp.
Kenjiro
K
Matsumoto
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, Togane, Japan.
Kanako
K
Takagi
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, Togane, Japan.
Atsumi
A
Kato
Laboratory of Toxicology and Applied Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, Togane, Japan.
Takuya
T
Ishibashi
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan.
Yasuo
Y
Mori
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, Togane, Japan.
Kimihito
K
Tashima
Laboratory of Toxicology and Applied Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, Togane, Japan.
Atsushi
A
Mitsumoto
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Japan.
Shinichi
S
Kato
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, Togane, Japan.
Syunji
S
Horie
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D064032:Calbindin 2 / Q000378:metabolism; D002135:Calcium-Binding Proteins; D003092:Colitis / Q000139:chemically induced / Q000150:complications; D003106:Colon / Q000294:innervation; D003911:Dextrans / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004576:Electromyography; D019054:Evoked Potentials, Motor / Q000187:drug effects / Q000502:physiology; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005727:Ganglia, Spinal / Q000166:cytology; D041981:Gastrointestinal Tract / Q000294:innervation / Q000378:metabolism; D006967:Hypersensitivity / Q000235:genetics / Q000378:metabolism*; D039001:Integrin alpha Chains / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058469:Receptors, Purinergic P2X / Q000378:metabolism; D013266:Stilbamidines / Q000493:pharmacokinetics; D013373:Substance P / Q000378:metabolism; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D059265:Visceral Pain / Q000209:etiology / Q000235:genetics / Q000378:metabolism*
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; C491049:Aif1 protein, mouse; D015703:Antigens, CD; D064032:Calbindin 2; D002135:Calcium-Binding Proteins; D003911:Dextrans; D039001:Integrin alpha Chains; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D058469:Receptors, Purinergic P2X; D013266:Stilbamidines; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; C091367:alpha E integrins; C015219:fluorescein isothiocyanate dextran; D013373:Substance P; D014302:Trinitrobenzenesulfonic Acid; D016650:Fluorescein-5-isothiocyanate
Enteric nervous system; Inflammatory bowel disease; Sensory nerve; TRPM2; Visceral hypersensitivity