title: Spinal administration of the monoacylglycerol lipase inhibitor JZL184 produces robust inhibitory effects on nociceptive processing and the development of central sensitization in the rat.
abstract: OBJECTIVE
  The cannabinoid receptor-mediated analgesic effects of 2-arachidonoylglycerol (2-AG) are limited by monoacylglycerol lipase (MAGL). 4-nitrophenyl 4-[bis (1,3-benzodioxol-5-yl) (hydroxy) methyl] piperidine-1-carboxylate (JZL184) is a potent inhibitor of MAGL in the mouse, though potency is reportedly reduced in the rat. Here we have assessed the effects of spinal inhibition of MAGL with JZL184 on nociceptive processing in rats.
  
  
  METHODS
  In vivo spinal electrophysiological assays in anaesthetized rats were used to determine the effects of spinal administration of JZL184 on spinal nociceptive processing in the presence and absence of hindpaw inflammation. Contributions of CB(1)  receptors to these effects was assessed with AM251. Inhibition of 2-oleoylglycerol hydrolytic activity and alterations of 2-AG in the spinal cord after JZL 184 were also assessed.
  
  
  RESULTS
  Spinal JZL184 dose-dependently inhibited mechanically evoked responses of wide dynamic range (WDR) neurones in naïve anaesthetized rats, in part via the CB(1)  receptor. A single spinal administration of JZL184 abolished inflammation-induced expansion of the receptive fields of spinal WDR neurones. However, neither spinal nor systemic JZL184 altered levels of 2-AG, or 2-oleoylglycerol hydrolytic activity in the spinal cord, although JZL184 displayed robust inhibition of MAGL when incubated with spinal cord tissue in vitro.
  
  
  CONCLUSIONS
  JZL184 exerted robust anti-nociceptive effects at the level of the spinal cord in vivo and inhibited rat spinal cord MAGL activity in vitro. The discordance between in vivo and in vitro assays suggests that localized sites of action of JZL184 produce these profound functional inhibitory effects.
  
  
  BACKGROUND
  This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, UK.
authors.forename: S G
authors.initials: SG
authors.lastname: Woodhams
authors.forename: A
authors.initials: A
authors.lastname: Wong
authors.forename: D A
authors.initials: DA
authors.lastname: Barrett
authors.forename: A J
authors.initials: AJ
authors.lastname: Bennett
authors.forename: V
authors.initials: V
authors.lastname: Chapman
authors.forename: S P H
authors.initials: SP
authors.lastname: Alexander
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001095:Arachidonic Acids / Q000378:metabolism; D052117:Benzodioxoles / Q000008:administration & dosage*; D002351:Carrageenan; D059333:Central Nervous System Sensitization / Q000187:drug effects; D004333:Drug Administration Routes; D063388:Endocannabinoids / Q000378:metabolism; D004983:Ethanolamines / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008071:Lipoprotein Lipase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000235:genetics; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010880:Piperidines / Q000008:administration & dosage*; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1; D013045:Species Specificity; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D052117:Benzodioxoles; D002351:Carrageenan; D063388:Endocannabinoids; D004983:Ethanolamines; D005989:Glycerides; D008071:Lipoprotein Lipase; D008994:Monoacylglycerol Lipases; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C534333:JZL 184; C022203:N-acylethanolamines; C094503:glyceryl 2-arachidonate; C505247:2-oleoylglycerol; C078814:anandamide