Diuretic effects of cannabinoid agonists in mice

Cannabinoids both increase urine output and decrease urinary frequency in human subjects. However, these effects have not been systematically evaluated in intact mice, a species commonly used to evaluate the effects of novel cannabinoids. The present studies investigated whether cannabinoid agonists reliably produce diuresis in mice at doses comparable to those that produce other cannabinoid effects and, further, identified the receptors that may mediate these effects. Diuretic effects were measured in male mice over 6h. In some studies, urine was collected and analyzed for electrolyte measurements. In other studies, agonist injections were preceded by pretreatment with cannabinoid CB1 or CB2 selective antagonists, including a peripherally constrained CB1 antagonist. Companion studies evaluated the antinociceptive effects of the cannabinoid agonists in a warm-water tail-withdrawal assay. Direct-acting cannabinoid CB1 agonists Δ(9)-tetrahydrocannabinol (THC), WIN 55,212, AM7418 and AM4054, had biphasic effects on diuresis, with peak diuretic effects occurring at lower doses than peak antinociceptive effects. Cannabinoid diuresis was similar to κ-opioid agonist-induced diuresis in terms of maximum effects with only moderate loss of Na(+). Antagonism studies indicate that the diuretic effects of cannabinoids are CB1-receptor mediated, with both central and peripheral components. These findings suggest that mice may provide a model for understanding the mixed effects of marijuana on urine output, as described in clinical studies, and aid in the development of targeted cannabinoid based therapies for bladder dysfunction.