Functional role of cannabinoid receptors in urinary bladder

Abstract

Cannabinoids, the active components of Cannabis sativa (maijuana), and their derivatives produce a wide spectrum of central and peripheral effects, some of which may have clinical applications. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to the general cannabinoid pharmacology. In recent years, studies on the functional role of cannabinoid receptors in bladder have been motivated by the therapeutic effects of cannabinoids on voiding dysfunction in multiple sclerosis patients. In this review, we shall summarize the literature on the expression of cannabinoid receptors in urinary bladder and the peripheral influence of locally and systemically administered cannabinoids in the bladder. The ongoing search for cannabinoid-based therapeutic strategies devoid of psychotropic effects can be complemented with local delivery into bladder by the intravesical route. A greater understanding of the role of the peripheral CB(1) and CB(2) receptor system in lower urinary tract is necessary to allow the development of new treatment for pelvic disorders.

Keywords: Bladder; cannabinoids; irritation; protein-coupled receptor; receptor expression.

Figure 1

Chemical Structures of classical synthetic cannabinoids, with a basic tricyclic dibenzopyran structure, which is also shared by the psychoactive principle (-) Δ⁹-THC from cannabis. Synthetic analog of (-) Δ⁹-THC is the drug known as dronabinol. Two other drugs nabilone and ajulemic acid are synthetic derivatives of a phase I metabolite of (-) Δ⁹-THC. They differ from (-) Δ⁹-THC in terms of the extra methyl groups and a ketonic or carboxyl group in place of methyl group at the ninth carbon position

Figure 2

The metabotropic CB₁ receptor exhibit 48% amino acid sequence identity with CB₂ receptors and both of them are negatively coupled to adenylyl cyclase to inhibit cyclic AMP that indirectly inhibit L-type Ca ^2 + channel. CB₁ receptors couple via pertussis toxin -sensitive Gi/o proteins to inhibit N⁻, and P/Qtype Ca^2 + channels and K + channels. The inhibitory effects of cannabinoids on Ca^2 + channels in nerve terminals are similar to other endogenous anti-nociceptive agents such as opioids.[14] GP1a (N-(Piperidin-1-yl)-1-(2,4-dichlorophenyl)-1,4- dihydro-6-methylindeno[1,2-c]pyrazole-3-carboxamide) is a highly selective CB₂ agonist with Ki values of 0.037 and 363 nM for CB₂ and CB₁, respectively. The Δ⁹-THC mimics the action of endocannabinoids and acts non-selectively on both CB₂ and CB₁ receptors

Figure 3

Proposed mechanism of locally administered cannabinoid agonist in irritated bladder. Bladder irritated by acetic acid, in the animal model, activates TRPV1 on urothelium and adjoining nerves to release CGRP. Irritation evoked release of CGRP is blocked by mixed CB₁/CB₂ agonist ajulemic acid entrapped into liposome that activates CB₁ and CB₂ receptors on bladder surface and nerves

Figure 4

Amplification plot from a typical real time PCR experiment to detect expression of CB receptors in human urothelium relative to housekeeping gene β- actin. The urothelium specimens were obtained from organ donors. M3000P instrument measures the fl uorescence of dsDNA intercalating dye SYBR Green twice in each PCR cycle. This infl ection point is called the cycle number (Ct) at which fl uorescent signal generated passes over threshold baseline. The Ct value was determined for each specimen to measure receptor expression

Figure 5

Cystometric effect of mixed CB₁/CB₂ receptor agonist, ajulemic acid on bladder irritation induced by infusion of acetic acid (0.125%). Rats were pretreated with either saline or ajulemic acid entrapped in liposomes. Baseline cystometry (CMG) was done under saline infusion prior to bladder irritation induced by acetic acid. Activation of local cannabinoid receptors in the bladder blunted the decrease in micturition interval MI induced by acetic acid. Decrease in MI is evident from reduced time interval between the peaks of cystometrogram of saline treated rat relative to rat treated with ajulemic acid. The urodynamic parameter, MI, indirectly represents sensory functions and reduced MI is an integrated response of irritated bladder