Cannabinoid receptors 1 and 2 are associated with bladder dysfunction in an experimental diabetic rat model

Objective To investigate diabetes-associated changes in urinary bladder expression of cannabinoid receptors 1 and 2 (CB1 and CB2) and the functional role of CB agonists and antagonists in mediating phasic contractions of isolated bladder strips using a streptozotocin-induced diabetic rat model. Materials and Methods The bladder and dorsal root ganglion (DRG) were removed from diabetic rats and age-matched controls 8-10 weeks after diabetes induction. Expression of CB1 and CB2 mRNA was studied using quantitative real-time PCR and protein levels were determined by Western blot analysis. The effect of increasing concentrations (0.1-100M) of the mixed CB1/CB2 agonist R(+)-WIN 55,212-2 (WIN), selective CB1 antagonist (AM251) and selective CB2 antagonist (AM630) on carbachol-evoked contraction of bladder strips from control and diabetic rats was investigated. WIN-induced alterations of bladder strip contraction were then studied after pre-incubation with AM251 and AM630. Results Diabetes induced decreased CB1 protein and mRNA expression in both the bladder and DRG (P < 0.05), while decreased CB2 expression was observed in the bladder (P < 0.05). WIN decreased the amplitude, but not frequency, of carbachol-induced phasic contractions of bladder strips in a concentration-dependent manner and this effect was diminished in the diabetic state. AM630 and AM251 had no effect on isolated detrusor muscle function. Moreover, pre-incubation with AM251 partially counteracted the effect of WIN on detrusor muscle contraction. Conclusion The results indicate that CB1 and CB2 are responsible for the pathogenesis of bladder dysfunction in diabetes mellitus and represent a viable target for pharmacological treatment of bladder cystopathy.