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

Abstract

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 (0.1-100 mM) 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.

Metabolic Syndrome Induced Bladder Cannabinoid Receptor Changes in the Fructose‐Fed Rats

“…The main finding of this study was the decreased genetic expressions of FR bladder CB1/CB2 receptors associated with reduced relaxation response towards Bay59‐3047. Relevant to our results, a prior study in streptozotocin‐induced type‐1 diabetic rats demonstrated decreased bladder CB1/CB2 protein and mRNA expressions . In the FR model, increase in serum insulin usually occurs 2–3 weeks after diet change while increase in serum sugar level after 6 weeks.…”

“…Relevant to our results, a prior study in streptozotocin-induced type-1 diabetic rats demonstrated decreased bladder CB1/CB2 protein and mRNA expressions. 23 In the FR model, increase in serum insulin usually occurs 2-3 weeks after diet change while increase in serum sugar level after 6 weeks. There is a time lag between insulin resistance and the development of type-2 diabetes.…”

Induction of Proteinuria by Cannabinoid Receptors 1 Signaling Activation in CB1 Transgenic Mice

“…Cannabinoid abuse is thus a potent risk factor for renal disorders in human subjects. 26 Several metabolic disorders respond to high glucose stress by triggering CB1 action, which can induce bladder dysfunction, 27 neuropathic pain 28 and coronary artery disease. 29 Upregulation of proteinuria in rat kidneys by WIN55212-2 also further explains the deleterious effect of CB1 on renal homeostasis.…”

Functional and Molecular Characterization of Hyposensitive Underactive Bladder Tissue and Urine in Streptozotocin-Induced Diabetic Rat

“…The upregulation of EP1 and EP3 receptors in DBD may be compensatory changes to maintain bladder contractility [35], [36]. DBD is also known to cause alteration in expression of cannabinoid and TRPV1 receptors in bladder and urinary tract [37], [38].…”