Faculty Collaboration Database

Blockade of endocannabinoid hydrolytic enzymes attenuates precipitated opioid withdrawal symptoms in mice. J Pharmacol Exp Ther 2011 Oct;339(1):173-85

Date

07/02/2011

Pubmed ID

21719468

Pubmed Central ID

PMC3186294

DOI

10.1124/jpet.111.181370

Scopus ID

2-s2.0-80053144160 (requires institutional sign-in at Scopus site)   93 Citations

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.

Author List

Ramesh D, Ross GR, Schlosburg JE, Owens RA, Abdullah RA, Kinsey SG, Long JZ, Nomura DK, Sim-Selley LJ, Cravatt BF, Akbarali HI, Lichtman AH

Author

Gracious R. Ross Research Scientist II in the Cardiovascular Center department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amidohydrolases
Animals
Arachidonic Acid
Behavior, Animal
Benzodioxoles
Brain Chemistry
Cannabinoid Receptor Modulators
Diarrhea
Dronabinol
Electric Stimulation
Endocannabinoids
Hydrolysis
Ileum
Male
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Mice, Knockout
Monoacylglycerol Lipases
Morphine Dependence
Muscle Contraction
Naloxone
Narcotic Antagonists
Piperidines
Prostaglandins
Pyridines
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
Substance Withdrawal Syndrome
Weight Loss