title: Blockade of endocannabinoid hydrolytic enzymes attenuates precipitated opioid withdrawal symptoms in mice.
abstract: Δ(9)-Tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB(1) and CB(2) cannabinoid receptors, the role these receptors play in reducing the variety of opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this study was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces naloxone-precipitated morphine withdrawal symptoms in in vivo and in vitro models of opioid dependence. Morphine-dependent mice challenged with naloxone reliably displayed a profound withdrawal syndrome, consisting of jumping, paw tremors, diarrhea, and weight loss. THC and the MAGL inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) dose dependently reduced the intensity of most measures through the activation of CB(1) receptors. JZL184 also attenuated spontaneous withdrawal signs in morphine-dependent mice. The FAAH inhibitor N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide (PF-3845) reduced the intensity of naloxone-precipitated jumps and paw flutters through the activation of CB(1) receptors but did not ameliorate incidence of diarrhea or weight loss. In the final series of experiments, we investigated whether JZL184 or PF-3845 would attenuate naloxone-precipitated contractions in morphine-dependent ilea. Both enzyme inhibitors attenuated the intensity of naloxone-induced contractions, although this model does not account mechanistically for the autonomic withdrawal responses (i.e., diarrhea) observed in vivo. These results indicate that endocannabinoid catabolic enzymes are promising targets to treat opioid dependence.
authors: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298-0613, USA.
authors: Divya
authors: D
authors: Ramesh
authors: Gracious R
authors: GR
authors: Ross
authors: Joel E
authors: JE
authors: Schlosburg
authors: Robert A
authors: RA
authors: Owens
authors: Rehab A
authors: RA
authors: Abdullah
authors: Steven G
authors: SG
authors: Kinsey
authors: Jonathan Z
authors: JZ
authors: Long
authors: Daniel K
authors: DK
authors: Nomura
authors: Laura J
authors: LJ
authors: Sim-Selley
authors: Benjamin F
authors: BF
authors: Cravatt
authors: Hamid I
authors: HI
authors: Akbarali
authors: Aron H
authors: AH
authors: Lichtman
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D052117:Benzodioxoles / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D003967:Diarrhea / Q000517:prevention & control; D013759:Dronabinol / Q000494:pharmacology; D004558:Electric Stimulation; D063388:Endocannabinoids; D006868:Hydrolysis; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000235:genetics; D009021:Morphine Dependence / Q000150:complications*; D009119:Muscle Contraction / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000523:psychology; D015431:Weight Loss / Q000187:drug effects; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D016718:Arachidonic Acid; D052117:Benzodioxoles; D063385:Cannabinoid Receptor Modulators; D013759:Dronabinol; D063388:Endocannabinoids; D008994:Monoacylglycerol Lipases; D009270:Naloxone; D009292:Narcotic Antagonists; D010880:Piperidines; D011453:Prostaglandins; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C534333:JZL 184; C557973:PF 3845