KPR‐2579, a novel TRPM8 antagonist, inhibits acetic acid‐induced bladder afferent hyperactivity in rats

Aims Transient receptor potential melastatin 8 (TRPM8) is proposed to be a promising therapeutic target for hypersensitive bladder disorders. We examined the effects of KPR‐2579, a novel selective TRPM8 antagonist, on body temperature and on mechanosensitive bladder single‐unit afferent activities (SAAs) provoked by intravesical acetic acid (AA) instillation in rats. Methods Female Sprague‐Dawley rats were used. Effects of cumulative intravenous (i.v.) administrations of KPR‐2579 (0.03‐1 mg/kg) on deep body temperature were investigated (N = 18). In separate animals, effects of bolus administration of KPR‐2579 (0.03 or 0.3 mg/kg, i.v.) on bladder hyperactivity induced by intravesical instillation of 0.1% AA were investigated using cystometry (N = 57) in a conscious free‐moving condition or urethane‐anesthetized condition, and SAA measurements (N = 41) were performed in a urethane‐anesthetized condition. Results KPR‐2579 at any doses tested did not affect body temperature. In cystometry measurements, a high dose (0.3 mg/kg) of KPR‐2579 counteracted the shortened intercontraction interval provoked by AA instillation. In SAA measurements, 48 single afferent fibers (n = 24 in each fiber) were isolated. AA instillations significantly increased the SAAs of C fibers, but not of Aδ fibers, in the presence of KPR‐2579's vehicle and a low dose (0.03 mg/kg) of KPR‐2579. Pretreatment with a high dose (0.3 mg/kg) of KPR‐2579 significantly inhibited the AA‐induced activation of C‐fiber SAAs. Conclusion The present results suggest that TRPM8 channels play a role in the AA‐induced pathological activation of mechanosensitive bladder C fibers in rats. KRP‐2579 may be a promising drug for hypersensitive bladder disorders.