Effects of IP-751, Ajulemic Acid, on Bladder Overactivity Induced by Bladder Irritation in Rats

ObjectivesAjulemic acid (IP-751) is a synthetic analog of tetrahydrocannabinol, which is a major ingredient of the plant Cannabis. IP-751 reportedly shows potent anti-inflammatory activity and is a powerful analgesic agent. Thus, we examined whether IP-751 can suppress urinary frequency induced by nociceptive stimuli in the bladder.MethodsContinuous cystometry (infusion rate 0.04 mL/min) under urethane anesthesia was performed to evaluate the effect of intravenous injection of IP-751 with or without a cannabinoid-1 receptor antagonist (AM251) or a cannabinoid-2 receptor antagonist (AM630) on bladder function in normal rats and rats with urinary frequency induced by intravesical infusion with 0.25% acetic acid or cyclophosphamide (CYP) (150 mg/kg intraperitoneally, 48 hours before cystometrography).ResultsWhen 10 mg/kg of IP-751 was injected in normal rats, the intercontraction interval (ICI) and pressure threshold increased. A 0.25% acetic acid infusion induced urinary frequency, as evidenced by a reduction in ICIs, which were suppressed by injection of IP-751 (10 mg/kg). Urinary frequency, indicated by significant ICI reductions, was also observed in the CYP-treated rats. Administration of IP-751 (10 mg/kg) significantly suppressed CYP-induced urinary frequency, as evidenced by the increase in the ICI. When AM251, but not AM630, was administered before IP-751, the IP-751-induced increases in the ICI and pressure threshold were prevented in all three groups. In addition, administration of AM251 alone decreased the ICIs in CYP-treated rats.ConclusionsIP-751 can suppress normal bladder activity and urinary frequency induced by bladder nociceptive stimuli, probably by suppression of bladder afferent activity. These inhibitory effects of IP-751 are at least in part mediated by the cannabinoid-1 receptor.