The Cannabinoid Agonist WIN55,212-2 Suppresses Opioid-induced Pruritus in Mice

Lee, Heeseung

Abstract

BACKGROUND: Cannabinoid receptor agonists can reverse opioidinduced nausea and vomiting in animals, but have not yet been tested against opioid-induced pruritus. This study tests the hypothesis that a cannabinoid receptor agonist will prevent opioidinduced pruritus and evaluates if the use of a cannabinoid receptor agonist will increase the analgesic efficacy of opioids.
METHODS
Various doses of fentanyl were injected subcutaneously in mice to obtain a dose-response curve with the use of a writhing test. To observe the analgesic potentiation of the cannabinoid agonist WIN55,212-2 in the writhing test, mice were pretreated with various concentrations of WIN55,212-2 (0.25, 0.5, 1.0, 2.0 mg/kg) 10 min prior to the injection of an ED50 dose of fentanyl, as determined from the dose-response curve. To observe the antipruritogenic effect of WIN55,212-2 in a scratching test, mice were pretreated with WIN55,212-2 (0.25, 0.5 mg/kg) 20 min prior to fentanyl injection. A CB1 receptor selective antagonist, AM251 (3 mg/kg), was used to confirm the cannabinoid receptor selectivity.
RESULTS
The ED50 of fentanyl in the writhing test was 0.018 mg/kg (range, 0.011?0.025 mg/kg). A dose of 1 mg/kg WIN55,212-2 increased the analgesic efficacy of fentanyl significantly (P < 0.001), but doses of 0.25 mg/kg and 0.5 mg/kg did not increase the analgesic efficacy. A dose of 0.25 mg/kg WIN55,212-5 reduced the scratching response of fentanyl significantly (P < 0.001) and this action was a cannabinoid receptor selective response.
CONCLUSIONS
These results demonstrate that 0.25 mg/kg WIN55,212-2 can prevent opioid-induced pruritus. The antipruritogenic activity of WIN55,212-2 occurs at CB1 receptors even if the analgesic efficacy of fentanyl cannot be increased.