Nausea and vomiting are the common side effects associated with cancer chemotherapy that profoundly affects the patients' quality of life and may lead to refusal of further chemotherapy treatment. Several classes of drugs (dopamine D2 receptor antagonists, serotonin 5-HT3 receptor antagonists and cannabinoid agonists) appear to be useful in the prevention of chemotherapeutically-induced emesis. Unlike D2- and 5-HT3- receptor antagonists, the mechanism of the antiemetic action of clinically useful cannabinoids is presently unknown. However, basic and clinical studies clearly show that delta-9- tetrahydrocannabinol (delta9-THC) and its synthetic analog nabilone, demonstrate significant antiemetic efficacy. The recent developments of selective antagonists for cannabinoid CB1 and CB2 receptors, as well as the introduction, and pharmacological characterization of a versatile, inexpensive, new animal model of emesis [the least shrew (Cryptotis parva)]; provide the opportunity to investigate the cannabinoid receptor mechanisms responsible for their antiemetic actions. The chemotherapeutic agent cisplatin is the most potent emotogenic substance both in animals and man. Cisplatin administration also produces emesis in the least shrew in a dose- and time-dependent manner. Moreover, both delta9-THC and 5-HT3 receptor antagonists prevent the cisplatin-induced vomiting in this species. On the other hand, 5-HT3- and D2-receptor agonists, potently and rapidly induce vomiting in the least shrew. Pretreatment with either delta9-THC or D2-receptor antagonists prevent the emesis produced by apomorphine (a dopamine D2 agonist) in the least shrew). The specific goals of this investigation are:
Specific aim 1) a) To investigate which cannabinoid receptor(s) is responsible for the antiemetic action of delta9-THC in blocking the ability of the chemotherapeutic agent, cisplatin, to produce emesis; b) to determine the presence of the implicated antiemetic cannabinoid receptor(s) by radioligand binding techniques; c) to find whether delta9-THC's antiemetic activity is shared by the well known representatives of other classes of cannabinoid agonists (methanandamide, CP, 55, 940 and WIN 55, 212-2).
Specific aim 2) To establish the pharmacological profile of delta9-THC and related derivatives in the least shrew in order to determine whether other behavioral effects contribute to the antiemetic properties fo cannabinoids.
Specific aim 3) Since delta9-THC potently blocks the ability of apomorphine (a D2 agonist) to induce emesis in the cat and the least shrew, the cannabinoid receptors responsible for this effect will be characterized. The ability of delta9-THC to inhibit emesis produced by the 5-HT3, agonist, 2-methyl 5-HT, will be also investigated. The results will define an important role for the cannabinoid receptors in the vomiting circuits and may implicate an antiemetic role for the endogenous cannabinoids.
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