MECHANISMS OF CANNABINOID'S ANTIEMETIC ACTIONS

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DESCRIPTION (provided by applicant): Chemotherapy induces emesis in two phases, immediate and delayed. The immediate phase of vomiting induced by chemo- or radiotherapy can be treated with serotonin 5-HT3 receptor antagonists, however, there is currently no clinically available antiemetic or antiemetic combination therapy that is effective in all patients either for the immediate or the delayed phase. Moreover, although clinical trials indicate that addition of dexamethasone and/or substance P receptor antagonists improve the antiemetic activity of 5-HT3 antagonists in both acute and delayed emesis, these agents are not effective in all patients. (9- Tetrahydrocannabinol ((9-THC) and its synthetic analog, nabilone, are effective antiemetics against chemo- and radiotherapy, and patients who are protected during the immediate phase also respond well during the delayed phase. Recent animal studies have shown that xenobiotic cannabinoids of diverse structure and activity ((9-THC, CP 55, 940 and WIN 55, 212-2) have broadspectrum antiemetic efficacy via cannabinoid CB1 receptors. Indeed, (9-THC and its analogs prevent the acute phase of cisplatin-induced emesis at doses which do not significantly suppress spontaneous motor activity in the least shrew (Cryptotis parva). The goals of this proposal are to define the broadspectrum antiemetic nature of cannabinoids against both the immediate and delayed phases of emesis produced by chemo and radiotherapy as well as revealing by behavioral and biochemical means whether tolerance develop to the antiemetic capacity of xenobiotic cannabinoids. The specific aims are: 1) Further characterization and mechanistic evaluation of broadspectrum antiemetic potential of xenobiotic cannabinoids ((9-THC, WIN 55, 212-2, CP 55, 940) in the least shrew against diverse emetic stimuli such as radiation, substance P and cisplatin-induced delayed emesis; 2) To show whether co-administration of (9-THC can potentiate the antivomiting efficacy of established antiemetics (serotonin 5-HT3-, dopamine D2- and neurokinin NK1-receptor antagonists and dexamethasone) against chemo- and radiotherapy-induced vomiting; 3) Determination of relative development of tolerance to antiemetic and motor suppressive effects of (9-THC by means of behavioral studies, radioligand binding and G-protein assays. The results will have important implications for the therapeutic utility of these "agonist antiemetics".