Colonic mucosal N-methyl-D-aspartate receptor mediated visceral hypersensitivity in a mouse model of irritable bowel syndrome

Abstract

Aim

The molecular mechanism of visceral hypersensitivity in irritable bowel syndrome (IBS) is not clear. Previous studies pointed primarily to the enhancements in the central and peripheral sensitization. The aim of this study was to investigate whether colonic mucosal N-methyl-D-aspartate receptor (NMDAR) participated in the visceral hypersensitivity in IBS.

Methods

C57BL/6 mice were administered intrarectally with trinitrobenzenesulfonic acid (TNBS) for the establishment of an IBS-like visceral hypersensitivity model. Abdominal withdrawal reflex (AWR) scores in response to colorectal distention were used to assess the visceral sensitivity. NMDAR levels in the colonic mucosa were detected by immunohistochemistry and western blot. The concentrations of glutamate and ammonia in feces of mice were measured. Changes of visceral sensitivity after intracolonic administration of ammonia or NMDAR antagonist were recorded.

Results

We established an IBS-like mouse model featured as visceral hypersensitivity with no evident inflammation in the colon. NMDAR levels in colonic mucosa of IBS-like mice were significantly higher compared to controls, and were positively associated with AWR scores. The glutamate level in the feces of TNBS mice was similar to controls, but the ammonia level was significantly higher than that of controls. Intracolonic administration of ammonia induced visceral hypersensitivity in mice, which was repressed by pretreatment with NMDAR antagonist.

Conclusions

The over-expressed NMDAR in colonic mucosa may participate in the pathogenesis of visceral hypersensitivity in IBS. Our study identifies the effect of ammonia in colonic lumen on NMDAR in colonic mucosa, as a potential novel targeted mechanism for IBS treatment.

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