THE EFFECT OF THE ENZYME-INHIBITOR PHENYLMETHYLSULFONYL FLUORIDE ON THE PHARMACOLOGICAL EFFECT ON ANANDAMIDE IN THE MOUSE MODEL OF CANNABIMIMETIC ACTIVITY

Anandamide is an putative endogenous cannabinoid ligand that produces pharmacological effects similar to those of Delta(9)-tetrahydrocannabi nol, the principle psychoactive constituent in marijuana. There is con siderable evidence that ?he enzyme inhibitor phenylmethylsulfonyl fluo ride (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 alterin g endogenous levels of anandamide as well as determining whether PMSF could potentiate the effects of exogenously administered anandamide, M ice receiving i.p, injections of PMSF exhibited cannabinoid effects th at included antinociception, hypothermia and immobility with ED50 valu es of 86, 224 and 206 mg/kg, respectively. Spontaneous activity was re duced at doses greater than 100 mg/kg. However,none of these effects w as blocked by the cannabinoid antagonist SR 141716A. On the other hand , pretreatment with an inactive dose of PMSF (30 mg/kg) potentiated th e effects of anandamide on tail-flick response (antinociception), spon taneous activity and mobility by 5-, 10- and 8-fold, respectively. PMS F did not alter anandamide's hypothermic effects. Overall, these findi ngs with PMSF underscore the importance of metabolism in the actions o f anandamide. It still must be established whether metabolites of anan damide contribute to its pharmacological activity.