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.