Anandamide transporter-mediated regulation of the micturition reflex in urethane-anesthetized rats

The aim of this study was to investigate the effects of an anandamide transporter inhibitor that can increase endogenous anandamide concentration on the micturition reflex in urethane-anesthetized rats. Continuous cystometrograms were performed in female Sprague-Dawley rats under urethane anesthesia. After stable micturition cycles were established, VDM11 (1, 3 and 10 mg/kg), an anandamide membrane transporter inhibitor, was administered intravenously to evaluate changes in bladder activity. In experiments examining the effects of cannabinoid (CB) receptor antagonists, VDM11 (10 mg/kg) was injected intravenously when the first bladder contraction was observed after intravenous administration of AM251, a CB1 receptor antagonist (3 mg/kg), or AM630, a CB2 receptor antagonist (3 mg/kg). Intravenous administration of VDM11 increased intercontraction intervals and threshold pressure at doses of 3 mg/kg or higher in dose-dependent fashion. When AM251 was administered one voiding cycle before VDM11 administration, the increases in intercontraction intervals and threshold pressure induced by VDM11 administration alone were not seen. In contrast, when AM630 was administered before VDM11 administration, increases in intercontraction intervals and threshold pressure were observed, as they were after VDM11 alone. These results suggest that anandamide, an endogenous CB ligand, can modulate the micturition reflex and that anandamide transporters play an important role in this modulation. In urethane-anesthetized rats, inhibition of the uptake of anandamide can inhibit the micturition reflex and these inhibitory effects of VDM11 are at least in part mediated by the CB1 receptor.