Elevation of Endocannabinoids via Inhibition of their Catabolic Enzymes Attenuates the Precipitated Opioid Withdrawal Syndrome

Abstract

It has long been known that cannabis and its primary active constituent, Δ9‐tetrahydrocannbinol (THC), reduce opioid withdrawal symptoms. The endocannabinoids, anandamide (AEA) and 2‐arachidonyl glycerol (2‐AG), also activate CB1 receptors, but they are rapidly metabolized by their respective enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The objective of this study was to determine whether elevating AEA or 2‐AG, via selective pharmacological inhibition of their metabolizing enzymes, would reduce precipitated morphine withdrawal symptoms. ICR mice were implanted subcutaneously with morphine pellets and challenged 72 h later with the opioid receptor antagonist, naloxone, to precipitate withdrawal. The withdrawal signs included number of jumps, paw tremors, head twitches, body weight loss and the occurrence of diarrhea. Pretreatment with the MAGL inhibitor, JZL184 dose‐dependently reduced the intensity of all naloxone‐precipitated withdrawal signs and these effects were reversed by the CB1R antagonist rimonabant, but not by the CB2R antagonist SR144528, suggesting a CB1 receptor specific mechanism of action. The FAAH inhibitor, PF‐3845 reduced the intensity of naloxone precipitated jumps and paw flutters through a CB1 receptor mechanism, but did not affect other withdrawal signs. The results from the present study are the first to show that the elevation of endocannabinoids ameliorates the expression of opioid withdrawal. Thus, the enzymes responsible for endocannabinoid degradation offer promising targets for possible new treatments for opioid dependence.