We evaluated the effects of GRC-6211, an orally active TRPV1 antagonist, on the function and noxious input of naïve and inflamed bladders. In urethane (Sigma(R)) anesthetized rats 0.5 ml GRC-6211 (0.001, 0.01, 0.1 and 1 mg/kg weight) or its vehicle (0.5% methylcellulose) were administered through a duodenal catheter and cystometry was done during infusion of saline, 100 microM capsaicin or 0.5% acetic acid (Merck, Feltham, United Kingdom). Cystometry was also performed in WT and TRPV1 knockout mice treated with 1 mg/kg GRC-6211. Cystometry was done in rats inflamed with lipopolysaccharide after receiving 0.1 mg/kg GRC-6221 or vehicle. Spinal c-fos expression induced by 0.5% acetic acid was investigated after 0.1 mg/kg GRC-6211 or vehicle administration. TRPV1 immunoreactivity was evaluated in the bladder after GRC-6211 administration. The reflex activity of rat and WT mice naïve bladders was unchanged by GRC-6211 up to a dose of 0.1 mg/kg. At 1 mg/kg contractions were transiently suppressed in naïve rats and WT mice but not in TRPV1 knockout mice. GRC-6211 (0.1 mg/kg) completely prevented capsaicin induced irritation, while the 0.001, 0.01 or 0.1 mg/kg dose decreased the mean +/- SD frequency of bladder contractions during acetic acid infusion from 1.5 +/- 0.3 to 1.35 +/- 0.35 (not significant), 0.9 +/- 0.2 (p <0.05) and 0.8 +/- 0.2 (p <0.05), respectively. Lipopolysaccharide inflamed rats had 1.4 +/- 0.4 and 0.8 +/- 0.1 contractions per minute after vehicle and GRC-6211, respectively (p <0.05). The c-fos expression induced by acetic acid was decreased by GRC-6211 (85.5 +/- 19.1 to 46.7 +/- 9.4, p <0.05). GRC-6211 did not change bladder TRPV1 immunoreactivity. GRC-6211 counteracts the bladder hyperactivity and noxious input induced by cystitis. At high doses it suppresses normal bladder activity by a TRPV1 dependent mechanism. TRPV1 antagonists might be useful for cystitis.

We evaluated the role of transient receptor potential vanilloid subfamily 1 for the generation of noxious bladder input and bladder overactivity associated with cystitis. Spinal c-fos expression triggered by innocuous bladder distention (10 cm water) was studied in sham and lipopolysaccharide inflamed transient receptor potential vanilloid subfamily 1 +/+ and -/- mice. Bladder reflex activity was studied using urethane anesthesia in sham and lipopolysaccharide inflamed transient receptor potential vanilloid subfamily 1 +/+ and -/- mice. Inflammatory changes in the bladder of transient receptor potential vanilloid subfamily 1 +/+ and -/- mice were identical. Bladder distention in sham inflamed +/+ mice induced a mean +/- SD of 4 +/- 2 Fos cells per section. Bladder distention after lipopolysaccharide inflammation increased Fos cells to 34 +/- 5 (p 0.05). During saline infusion of sham inflamed bladders in +/+ mice 0.46 +/- 0.14 contractions per minute were documented. In lipopolysaccharide inflamed +/+ mice that frequency was increased to 1.13 +/- 0.12 contractions per minute (p 0.05). Our data demonstrate that transient receptor potential vanilloid subfamily 1 is essential for the generation of noxious bladder input and bladder overactivity associated with cystitis.