Abstract
Anandamide is an putative endogenous cannabinoid ligand that produces pharmacological effects similar to those of Δ9-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.
Footnotes
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Send reprint requests to: Billy R. Martin, Ph.D., P.O. Box 980613, Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613.
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↵1 This research was supported by NIDA grants DA 09789 and DA 08677.
- Abbreviations:
- i.v.
- intravenous
- i.p.
- intraperitoneal
- THC
- tetrahydrocannabinol
- % MPE
- percent maximal possible effect
- ED50
- dose effectively producing 50% of maximal response
- C.L.
- confidence limits
- Δ°C
- change in rectal temperature in degrees Celsius
- PMSF
- phenylmethylsulfonyl fluoride
- Received May 19, 1997.
- Accepted August 22, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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