The overall goal of this proposal is to provide further evidence for a mechanism of action for cannabinoids in which prostaglandins are important mediators. Previous work has shown that THC and other cannabinoids cause major changes in arachidonic acid metabolism in a variety of systems both in vitro and in vivo. These, in turn, lead to changes in prostaglandin levels which may affect c-AMP production and/or cause neurotransmitter mediated effects. In this application, experiments are proposed which will attempt to show a casual relationship between THC-induced prostaglandin changes and catalepsy and/or motor toxicity in the mouse. The role of lipid metabolism changes during the development of, and recovery from tolerance to THC will provide a second approach to the question of mechanism. Other approaches will involve the study of THC responses in mice actively immunized against PGE2 and the study of arachidonate metabolism in mouse strains with different responses to THC. Finally, studies on the role of the major metabolite, delta1-THC- 7-oic acid, in the pharmacodynamics of THC will be continued with special regard to its inhibitory effects on prostaglandin synthesis. A better understanding of the mechanism of action of THC is needed to (1) design experiments aimed at furthering our knowledge of the health related consequences of cannabis use (2) provide a rational basis for exploring the therapeutic uses of cannabinoids and (3) improve our understanding of a unique class of drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA002043-12
Application #
3207092
Study Section
(SRCD)
Project Start
1977-09-01
Project End
1993-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
12
Fiscal Year
1988
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
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
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
Burstein, S H (1987) Inhibitory and stimulatory effects of cannabinoids on eicosanoid synthesis. NIDA Res Monogr 79:158-72
Burstein, S; Hunter, S A; Latham, V et al. (1987) A major metabolite of delta 1-tetrahydrocannabinol reduces its cataleptic effect in mice. Experientia 43:402-3

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