Δ9-Tetrahydrocannabinol and Synthetic Cannabinoids Prevent Emesis Produced by the Cannabinoid CB1 Receptor Antagonist/Inverse Agonist SR 141716A

Abstract

There is substantial clinical evidence that Δ9-tetrahydrocannabinol (Δ9-THC) and its synthetic analogs (nabilone and levonantradol) can prevent emesis in cancer patients receiving chemotherapy. Limited available animal studies also support the antiemetic potential of these cannabinoids. The present study investigates the mechanism of antiemetic action of cannabinoids in an established animal model of emesis, the least shew (Cryptotis parva). Since cannabinoid agonists prevent emesis, it was hypothesized that blockade of either the cannabinoid CB1 receptor or the cannabinoid CB2 receptor would induce vomiting. Thus, the emetic potential of SR 141716A (CB1 receptor antagonist) or SR 144528 (CB2 receptor antagonist) was investigated. Both intraperitoneal (0, 1, 2.5, 5, 10 and 20 mg/kg, n = 7–15 per group) and subcutaneous (0, 10, 20 and 40 mg/kg, n = 6–9 per group) administration of SR 141716A caused emesis (ED50 = 5.52 ± 1.23 and 20.2 ± 1.02 mg/kg, respectively) in the least shrew in a dose-dependent manner. Indeed, both the frequency of emesis and the percentage of animals vomiting increased with increasing doses of SR 141716A. Significant effects were seen at the 10- and 20-mg/kg doses for the IP route, while only the 40-mg/kg dose produced significant emesis via the SC route. The CB2 antagonist failed to produce emesis via either route of administration. SR 141716A at an IP dose of 20 mg/kg was used to induce emesis for drug interaction studies. Thus, varying doses of three different classes of cannabinoid agonists [CP 55, 940 (0, 0.1, 0.5 and 1 mg/kg), WIN 55, 212-2 (0, 1, 5 and 10 mg/kg), and Δ9-THC (0, 5, 10 and 20 mg/kg)], were administered IP to different groups of shrews 10 min prior to SR 141716A injection. The frequency of emesis was recorded for 30 min following the administration of SR 141716A. The order of potency for redcing both the frequency of emesis and the percentage of shrews vomiting was CP 55, 940 > WIN 55, 212-2 > Δ9-THC which is consistent with an action on the CB1 receptor. These results suggest that the antiemetic activity of Δ9-THC and its synthetic analogs reside in their ability to stimulate the cannabinoid CB1 receptor. Furthermore, the antiemetic potency of CP 55, 940 is 45 times greater than Δ9-THC. On the other hand, blockade of CB1 receptors can induce vomiting, which implicates an important role for endogenous cannabinoids in emetic circuits.