Combined peripheral cannabinoid CB1 and CB2 receptor activation abolishes cystitis-induced bladder hyperalgesia

Cannabinoid agonists may ameliorate bladder pain associated with interstitial cystitis/bladder pain syndrome. Visceromotor responses (VMRs) to bladder distension were recorded in urethane-anesthetised control and protamine/zymosan-treated guinea pigs. The peripherally restricted preferential CB1 receptor agonist PrNMI and the selective CB2 receptor agonist 4Q3C each reduced cystitis-induced enhancement of VMRs at high intravesical pressures. Co-activation of CB1 and CB2 receptors abolished cystitis-induced bladder hyperalgesia. These findings indicate that simultaneous targeting of peripheral CB1 and CB2 receptors may provide clinically meaningful benefits for the treatment of bladder pain associated with cystitis.