There is substantial clinical evidence that
Delta(9)-tetrahydrocannabinol (Delta(9)-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 CB(1) receptor or the
cannabinoid CB(2) receptor would induce
vomiting. Thus, the
emetic potential of
SR 141716A (CB(1) receptor antagonist) or
SR 144528 (CB(2) 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 (ED(50) = 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 CB(2) 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
Delta(9)-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 >
Delta(9)-THC which is consistent with an action on the CB(1) receptor. These results suggest that the
antiemetic activity of
Delta(9)-THC and its synthetic analogs reside in their ability to stimulate the
cannabinoid CB(1) receptor. Furthermore, the
antiemetic potency of CP 55, 940 is 45 times greater than
Delta(9)-THC. On the other hand, blockade of CB(1) receptors can induce
vomiting, which implicates an important role for endogenous
cannabinoids in
emetic circuits.