Complementary genetic and pharmacological approaches to inhibit the monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), the primary hydrolytic enzymes of the respective endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA), enable the exploration of potential therapeutic applications and physiological roles of these enzymes. Complete and simultaneous inhibition of both FAAH and MAGL produces greatly enhanced cannabimimetic responses, including increased antinociception, and other cannabimimetic effects, far beyond inhibition of either enzyme alone. While CB1 receptor function is maintained following chronic FAAH inactivation, prolonged excessive elevation of brain 2-AG levels, via MAGL inhibition, elicits both behavioral and molecular signs of cannabinoid tolerance and dependence. Here, we evaluated the consequences of high dose of the MAGL inhibitor, JZL184 (40 mg/kg) given acutely or for six days in FAAH (-/-) and (+/+) mice. While acute administration of JZL184 to FAAH (-/-) mice enhanced the magnitude of a subset of cannabimimetic responses, repeated JZL184 treatment led to tolerance to its antinociceptive effects, cross-tolerance to the pharmacological effects of THC, decreases in CB1receptor agonist stimulated [35S]GTPγS binding, and dependence as indicated by rimonabant-precipitated withdrawal behaviors, regardless of genotype. Together, these data suggest that simultaneous elevation of both endocannabinoids elicits enhanced cannabimimetic activity, but MAGL inhibition drives CB1 receptor functional tolerance and cannabinoid dependence.
The American Society for Pharmacology and Experimental Therapeutics.

PMID:

 

24849924

 

[PubMed – as supplied by publisher]