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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA002052-13
Application #
3207101
Study Section
(SRCD)
Project Start
1977-10-01
Project End
1994-03-31
Budget Start
1989-05-01
Budget End
1990-03-31
Support Year
13
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Burstein, S H; Audette, C A; Breuer, A et al. (1992) Synthetic nonpsychotropic cannabinoids with potent antiinflammatory, analgesic, and leukocyte antiadhesion activities. J Med Chem 35:3135-41
Audette, C A; Burstein, S H; Doyle, S A et al. (1991) G-protein mediation of cannabinoid-induced phospholipase activation. Pharmacol Biochem Behav 40:559-63
Burstein, S (1991) Cannabinoid induced changes in eicosanoid synthesis by mouse peritoneal cells. Adv Exp Med Biol 288:107-12
Perez-Reyes, M; Burstein, S H; White, W R et al. (1991) Antagonism of marihuana effects by indomethacin in humans. Life Sci 48:507-15
Hunter, S A; Audette, C A; Burstein, S (1991) Elevation of brain prostaglandin E2 levels in rodents by delta 1-tetrahydrocannabinol. Prostaglandins Leukot Essent Fatty Acids 43:185-90
Doyle, S A; Burstein, S H; Dewey, W L et al. (1990) Further studies on the antinociceptive effects of delta 6-THC-7-oic acid. Agents Actions 31:157-63
Audette, C A; Burstein, S (1990) Inhibition of leukocyte adhesion by the in vivo and in vitro administration of cannabinoids. Life Sci 47:753-9
Burstein, S H; Hull, K; Hunter, S A et al. (1989) Immunization against prostaglandins reduces delta 1-tetrahydrocannabinol-induced catalepsy in mice. Mol Pharmacol 35:6-9
Burstein, S H; Audette, C A; Doyle, S A et al. (1989) Antagonism to the actions of platelet activating factor by a nonpsychoactive cannabinoid. J Pharmacol Exp Ther 251:531-5
Burstein, S H; Hull, K; Hunter, S A et al. (1988) Cannabinoids and pain responses: a possible role for prostaglandins. FASEB J 2:3022-6

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