The effect of the enzyme inhibitor phenylmethylsulfonyl fluoride on the pharmacological effect of anandamide in the mouse model of cannabimimetic activity.
Anandamide is an putative endogenous cannabinoid ligand that produces pharmacological effects similar to those of Delta9-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.
Compton
D R
DR
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0613, USA.
Martin
B R
BR
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D002186:Cannabinoids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology; D000077285:Rimonabant
D000700:Analgesics; D001095:Arachidonic Acids; D002186:Cannabinoids; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D010664:Phenylmethylsulfonyl Fluoride; D000077285:Rimonabant; C078814:anandamide