Selective Blockade of 2-arachidonoylglycerol Hydrolysis Produces Cannabinoid Behavioral Effects

Nat Chem Biol. 2009 Jan;5(1):37-44. doi: 10.1038/nchembio.129. Epub 2008 Nov 23.

Abstract

2-Arachidonoylglycerol (2-AG) and anandamide are endocannabinoids that activate the cannabinoid receptors CB1 and CB2. Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that for anandamide is mediated by fatty acid amide hydrolase (FAAH), and for 2-AG is thought to involve monoacylglycerol lipase (MAGL). FAAH inhibitors produce a select subset of the behavioral effects observed with CB1 agonists, which suggests a functional segregation of endocannabinoid signaling pathways in vivo. Testing this hypothesis, however, requires specific tools to independently block anandamide and 2-AG metabolism. Here, we report a potent and selective inhibitor of MAGL called JZL184 that, upon administration to mice, raises brain 2-AG by eight-fold without altering anandamide. JZL184-treated mice exhibited a broad array of CB1-dependent behavioral effects, including analgesia, hypothermia and hypomotility. These data indicate that 2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Animals
  • Arachidonic Acids / metabolism*
  • Behavior, Animal / drug effects*
  • Behavior, Animal / physiology
  • Benzodioxoles / chemistry
  • Benzodioxoles / pharmacology
  • Cannabinoids*
  • Dose-Response Relationship, Drug
  • Endocannabinoids
  • Glycerides / metabolism*
  • Hydrolysis / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monoacylglycerol Lipases / antagonists & inhibitors
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Cannabinoid, CB2 / metabolism

Substances

  • Arachidonic Acids
  • Benzodioxoles
  • Cannabinoids
  • Endocannabinoids
  • Glycerides
  • JZL 184
  • Piperidines
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • glyceryl 2-arachidonate
  • Monoacylglycerol Lipases
  • Amidohydrolases
  • fatty-acid amide hydrolase

Associated data

  • PubChem-Substance/56365468
  • PubChem-Substance/56365469
  • PubChem-Substance/56365470
  • PubChem-Substance/56365471
  • PubChem-Substance/56365472
  • PubChem-Substance/56365473
  • PubChem-Substance/56365474
  • PubChem-Substance/56365475
  • PubChem-Substance/56365476
  • PubChem-Substance/56365477
  • PubChem-Substance/56365478
  • PubChem-Substance/56365479
  • PubChem-Substance/56365480
  • PubChem-Substance/56365481
  • PubChem-Substance/56365482
  • PubChem-Substance/56365483
  • PubChem-Substance/56365484
  • PubChem-Substance/56365485
  • PubChem-Substance/56365486
  • PubChem-Substance/56365487
  • PubChem-Substance/56365488
  • PubChem-Substance/56365489
  • PubChem-Substance/56365490
  • PubChem-Substance/56365491
  • PubChem-Substance/56365492
  • PubChem-Substance/56365493
  • PubChem-Substance/56365494
  • PubChem-Substance/56365495
  • PubChem-Substance/56365496
  • PubChem-Substance/56365497
  • PubChem-Substance/56365498
  • PubChem-Substance/56365499