title: In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects.
abstract: OBJECTIVE
  Since monoacylglycerol lipase (MAGL) has been firmly established as the predominant catabolic enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), a great need has emerged for the development of highly selective MAGL inhibitors. Here, we tested the in vivo effects of one such compound, KML29 (1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(benzo[d][1,3]dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate).
  
  
  METHODS
  In the present study, we tested KML29 in murine inflammatory (i.e. carrageenan) and sciatic nerve injury pain models, as well as the diclofenac-induced gastric haemorrhage model. KML29 was also evaluated for cannabimimetic effects, including measurements of locomotor activity, body temperature, catalepsy, and cannabinoid interoceptive effects in the drug discrimination paradigm.
  
  
  RESULTS
  KML29 attenuated carrageenan-induced paw oedema and completely reversed carrageenan-induced mechanical allodynia. These effects underwent tolerance after repeated administration of high-dose KML29, which were accompanied by cannabinoid receptor 1 (CB1 ) receptor desensitization. Acute or repeated KML29 administration increased 2-AG levels and concomitantly reduced arachidonic acid levels, but without elevating anandamide (AEA) levels in the whole brain. Furthermore, KML29 partially reversed allodynia in the sciatic nerve injury model and completely prevented diclofenac-induced gastric haemorrhages. CB1 and CB2 receptors played differential roles in these pharmacological effects of KML29. In contrast, KML29 did not elicit cannabimimetic effects, including catalepsy, hypothermia and hypomotility. Although KML29 did not substitute for Δ(9) -tetrahydrocannabinol (THC) in C57BL/6J mice, it fully and dose-dependantly substituted for AEA in fatty acid amide hydrolase (FAAH) (-/-) mice, consistent with previous work showing that dual FAAH and MAGL inhibition produces THC-like subjective effects.
  
  
  CONCLUSIONS
  These results indicate that KML29, a highly selective MAGL inhibitor, reduces inflammatory and neuropathic nociceptive behaviour without occurrence of cannabimimetic side effects.
  
  
  BACKGROUND
  This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Ignatowska-Jankowska
authors.forename: S
authors.initials: S
authors.lastname: Ghosh
authors.forename: M S
authors.initials: MS
authors.lastname: Crowe
authors.forename: S G
authors.initials: SG
authors.lastname: Kinsey
authors.forename: M J
authors.initials: MJ
authors.lastname: Niphakis
authors.forename: R A
authors.initials: RA
authors.lastname: Abdullah
authors.forename: Q
authors.initials: Q
authors.lastname: Tao
authors.forename: S T
authors.initials: ST
authors.lastname: O' Neal
authors.forename: D M
authors.initials: DM
authors.lastname: Walentiny
authors.forename: J L
authors.initials: JL
authors.lastname: Wiley
authors.forename: B F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: A H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D052117:Benzodioxoles / Q000009:adverse effects / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002186:Cannabinoids / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D002853:Chromatography, Liquid; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry
chemical_list: C000601471:1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(benzo(d)(1,3)dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052117:Benzodioxoles; D002186:Cannabinoids; D004791:Enzyme Inhibitors; D010880:Piperidines; D008994:Monoacylglycerol Lipases
keywords: 2-arachidonoylglycerol; CB1; CB2; allodynia; cannabinoid; gastric haemorrhage; inflammatory pain; monoacylglycerol lipase; mouse; neuropathic pain