Short-term sensitization of colon mechano receptors is associated with long-term hypersensitivity to colon distention in the mouse

Background & Aims: Using a mouse model that reproduces major features of irritable bowel syndrome (long-lasting colon hypersensitivity without inflammation), we examined the contributions of 2 proteins, transient receptor potential vanilloid 1 (TRPV1) and add-sensing ion channel 3 (ASIC3), on development of behavioral hypersensitivity and assessed the function of colon mechanoreceptors of hypersensitive mice. Methods: Visceral nociceptive behavior was measured as the visceromotor response (VMR) to colorectal distention (CRD) before and after intracolonic treatment with zymosan or saline. Colon pathology was assessed in parallel experiments by quantifying myeloperoxidase activity, intralumenal pH, and tissue histology. Electrophysiologic experiments were performed on naive and zymosan-treated hypersensitive mice using an in vitro colon-pelvic nerve preparation. Results: Zymosan, but not saline, produced significant and persistent increases in the VMRs of control mice; zymosan produced nonsignificant increases in the VMRs in TRPV1 and ASIC3 knockout mice. Colon myeloperoxidase activity and pH were unaffected by either CRD or intracolonic treatments. Pelvic nerve mechanoreceptors recorded from zymosan-treated or naive mice had similar sensitivity to stretch of the colon. When applied acutely, zymosan sensitized muscular/mucosal. mechanoreceptors in both naive and hypersensitive mice. Conclusions: Zymosan produced sensitization of colon mechanoreceptors acutely in vitro and chronic (>= 7 weeks) behavioral hypersensitivity in the absence of inflammation. The behavioral hypersensitivity was partially dependent on both TRPV1 and ASIC3 because deletions of either of these genes blunted zymosan's effect, suggesting that these proteins may be important peripheral mediators for development of functional (ie, noninflammatory) visceral hypersensitivity.