am-630 and Urinary-Bladder--Overactive

This study was designed to evaluate the effects of CP55,940 on normal bladder function in vivo and examine whether it suppresses urinary frequency induced by nociceptive stimuli in the bladder. Cannabinoid receptor (CBR) activity may be involved in the regulation of bladder function. However, the role of CBR subtypes in micturition has yet to be established. CP55,940 is a synthetic analogue of tetrahydrocannabidiol, which is a psychoactive ingredient of the Cannabis plant.. Cystometry under urethane anaesthesia was performed to evaluate the effect of intravesical delivery of CP55,940 with or without administration of CB1 antagonist AM251 or CB2 antagonist AM630 on bladder function in female rats. The effects of CP55,940 were also examined in rats with urinary irritation induced by intravesical infusion of acetic acid.. Infusion of CP55,940 significantly (p < 0.05) increased micturition interval (MI) and bladder capacity (BC) by 52 % and decreased maximal voiding pressure (MP) by 25 %. Pretreatment with AM251 or AM630 before CP55,940 administration prevented CP55,940-induced increases in MI, BC and reduced MP. Acetic acid induced urinary frequency as evidenced by a reduction in MI and was suppressed by CP55,940.. CP55,940 decreases bladder activity and urinary frequency induced by nociceptive stimuli, probably by suppression of bladder afferent activity. Effects of CP55,940 were abolished by both CBR antagonists. This data implicates a role for the endocannabinoid system in bladder mechanoafferent function in rats. In addition, our results show that CP55,940 reverses urinary frequency exemplified in an overactive bladder model, suggesting it could be an effective treatment for patients with lower urinary tract symptoms.

Topics: Acetic Acid; Administration, Intravesical; Animals; Cannabinoid Receptor Agonists; Cyclohexanols; Disease Models, Animal; Female; Indoles; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Treatment Outcome; Urinary Bladder; Urinary Bladder, Overactive; Urination; Urodynamics

The cannabinoid receptors CB1 and CB2 are localized in the urinary bladder and play a role in the regulation of its function. We investigated the pathomechanisms through which hyperosmolarity induces detrusor overactivity (DO). We compared urinary bladder activity in response to blockade of CB1 and CB2 receptors using AM281 and AM630, respectively, in normal rats and after hyperosmolar stimulation. Experiments were performed on 44 rats. DO was induced by intravesical instillation of hyperosmolar saline. Surgical procedures and cystometry were performed under urethane anaesthesia. The measurements represent the average of 5 bladder micturition cycles. We analysed basal, threshold, and micturition voiding pressure; intercontraction interval; compliance; functional bladder capacity; motility index; and detrusor overactivity index. The blockage of CB1 and CB2 receptors diminished the severity of hyperosmolar-induced DO. In comparison with naïve animals the increased frequency of voiding with no significant effect on intravesical voiding pressure profile was observed as a result of the blockage of CB1 and CB2 receptors. These results demonstrate that hyperosmolar-induced DO is mediated by CB1 and CB2 receptors. Therefore, the cannabinoid pathway could potentially be a target for the treatment of urinary bladder dysfunction.

Topics: Administration, Intravesical; Animals; Cannabinoid Receptor Antagonists; Cannabinoids; Disease Models, Animal; Female; Indoles; Morpholines; Osmolar Concentration; Pyrazoles; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Saline Solution, Hypertonic; Signal Transduction; Urinary Bladder; Urinary Bladder, Overactive; Urination; Urodynamics