Contrasting effects of WIN 55212-2 on motility of the rat bladder and uterus.

Abstract

Both the uterus and bladder contain cannabinoid (CB) receptors whose functions are poorly understood. Here, in urethane-anesthetized female rats in metestrus, we simultaneously compared the effects of close-arterial injections of the cannabinoid receptor agonist WIN 55,212-2 (WIN2) on uterine contractions (amplitude and rate) and micturition thresholds (MT) assessed by cystometry. Five doses of WIN2 were delivered (0.01, 0.1, 0.5, 1, and 1.5 micromol/kg) in three groups: (1) controls; (2) after bladder inflammation with intravesicular turpentine; and (3) after bilateral hypogastric neurectomy (HYPX). In some rats, drugs were delivered via the tail vein. Regarding bladder, WIN2 dose-dependently reduced MTs in all groups. Both bladder inflammation and HYPX significantly increased this effect. Regarding uterus, WIN2 dose-dependently increased uterine contraction amplitude. Bladder inflammation or HYPX significantly decreased this effect. Coinjection of the CB1 antagonist SR141716A (SR) (1.5 micromol/kg) and WIN2 (0.5 micromol/kg) abolished or reduced the effects of WIN2 in both organs. SR alone had significant effects only after HYPX, reducing both MT and uterine contraction amplitude. The vehicle (0.4% DMSO) and inactive enantiomer S(-)-WIN 55,212-3 were both ineffective. Close-arterial injections of WIN2 (0.5 micromol/kg) produced significantly larger effects in both organs than tail vein injections. These results indicate that, whereas WIN2 reduces bladder motility, it mainly increases uterine motility, likely via CB1 receptors located in the two organs. The opposing effects of bladder inflammation and HYPX on the potency of WIN in the two organs suggest a neurally mediated viscero-visceral interaction in which bladder inflammation influences uterine CB1 sensitivity, possibly by inhibiting adrenergic input to the uterus.