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Vol. 283, Issue 3, 1138-1143, 1997
Department of Pharmacology and Toxicology, Medical College of
Virginia, Virginia Commonwealth University, Richmond, Virginia
Anandamide is an putative endogenous cannabinoid ligand that produces
pharmacological effects similar to those of
9-tetrahydrocannabinol, the principle psychoactive
constituent in marijuana. There is considerable evidence that the
enzyme inhibitor phenylmethylsulfonyl fluoride (PMSF) is capable of
altering the actions of anandamide in vitro by blocking
its metabolism. Therefore, studies were conducted in mice to determine
whether PMSF could produce cannabinoid effects by altering endogenous
levels of anandamide as well as determining whether PMSF could
potentiate the effects of exogenously administered anandamide. Mice
receiving i.p. injections of PMSF exhibited cannabinoid effects that
included antinociception, hypothermia and immobility with
ED50 values of 86, 224 and 206 mg/kg, respectively.
Spontaneous activity was reduced at doses greater than 100 mg/kg.
However, none of these effects was blocked by the cannabinoid
antagonist SR 141716A. On the other hand, pretreatment with an inactive
dose of PMSF (30 mg/kg) potentiated the effects of anandamide on
tail-flick response (antinociception), spontaneous activity and
mobility by 5-, 10- and 8-fold, respectively. PMSF did not alter
anandamide's hypothermic effects. Overall, these findings with PMSF
underscore the importance of metabolism in the actions of anandamide.
It still must be established whether metabolites of anandamide
contribute to its pharmacological activity.
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