The cannabinoid agonist WIN55,212-2 suppresses opioid-induced emesis in ferrets

Background: Cannabinoid receptor agonists reverse nausea and vomiting produ ced by chemotherapy and radiation therapy in animals and humans but have no t been tested against opioid-induced emesis, This study tests the hypothesi s that cannabinoid receptor agonists will prevent opioid-induced vomiting. Methods: Twelve male ferrets were used. They weighed 1.2-1.6 kg at the begi nning and 1.8-2.3 kg at the end of the experiments, All drugs were injected subcutaneously. WIN55,212-2, a mixed CB1-CB2 cannabinoid receptor agonist, was administered 25 min before morphine. Retches and vomits were counted a t 5-min intervals for 30 min after morphine injection. Results: Retching and vomiting responses increased with increasing morphine doses up to 1.0 mg/kg, above which the responses decreased. Previous admin istration of naloxone prevented morphine-induced retching and vomiting. WIN 55,212-2 dose-dependently reduced retching and vomiting. The ED,, was 0.05 mg/kg for retches and 0.03 mg/kg for vomits. At 0.13 mg/kg, retching decrea sed by 76% and vomiting by 92%. AM251, a CB1 receptor-selective antagonist, blocked the antiemetic actions of WIN55,212-2, but AM630, a CB2 receptor-s elective antagonist, did not. Conclusions: These results demonstrate that WIN55,212-2 pre vents opioid-in duced vomiting and suggest that the antiemetic activity of WIN55,212-2 occu rs at CB1 receptors. This is consistent with findings that CB1 receptors ar e the predominant cannabinoid receptors in the central nervous system and t hat antiemetic effects of cannabinoids appear to be centrally mediated.