This proposal contains several independent but related goals which were derived from our previous and ongoing studies on the mechanism of action of cannabinoids. The central hypothesis is that THC and other cannabinoids exert profound effects on lipid metabolism, in particular, the metabolism of arachidonic acid which results in significant change both in vitro and in vivo in the production of eicosanoids such as PGE2. In this scheme we have shown that while some cannabinoids can behave as agonists, others can act as antagonists. The present proposal will directly address the question of possible agonist-antagonist interactions of cannabinoids in models such as the cataleptic response in mice. Relative levels of THC and its acid metabolites, which represent an agonist-antagonist pair, will be measured and compared with tissue levels of eicosanoids and with biological endpoints such as catalepsy, analgesia and anti-edema effects. The establishment of such an interaction would help explain some of the poorly understood effects of THC. A further consequence of these findings would be some of the poorly understood effects of THC. A further consequence of these findings would be a basis for a more rational approach toward the development of therapeutic uses for cannabinoids. Finally, we will explore the possibility that cannabinoids, by virtue of their membrane altering properties, could be used in a new approach to the treatment of diseases of retroviral origin such as AIDs. Experiments will be done to see whether tolerable doses of non-psychoactive cannabinoids can significantly fluidize cell membranes in vivo. Such changes in membranes are believed to decrease the infectivity of retroviruses resulting in a moderation of the effects of the disease.
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