title: JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy.
abstract: Cisplatin has been used effectively to treat a variety of cancers but its use is limited by the development of painful peripheral neuropathy. Because the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) is anti-hyperalgesic in several preclinical models of chronic pain, the anti-hyperalgesic effect of JZL184, an inhibitor of 2-AG hydrolysis, was tested in a murine model of cisplatin-induced hyperalgesia. Systemic injection of cisplatin (1mg/kg) produced mechanical hyperalgesia when administered daily for 7 days. Daily peripheral administration of a low dose of JZL184 in conjunction with cisplatin blocked the expression of mechanical hyperalgesia. Acute injection of a cannabinoid (CB)-1 but not a CB2 receptor antagonist reversed the anti-hyperalgesic effect of JZL184 indicating that downstream activation of CB1 receptors suppressed the expression of mechanical hyperalgesia. Components of endocannabinoid signaling in plantar hind paw skin and lumbar dorsal root ganglia (DRGs) were altered by treatments with cisplatin and JZL184. Treatment with cisplatin alone reduced levels of 2-AG and AEA in skin and DRGs as well as CB2 receptor protein in skin. Combining treatment of JZL184 with cisplatin increased 2-AG in DRGs compared to cisplatin alone but had no effect on the amount of 2-AG in skin. Evidence that JZL184 decreased the uptake of [(3)H]AEA into primary cultures of DRGs at a concentration that also inhibited the enzyme fatty acid amide hydrolase, in conjunction with data that 2-AG mimicked the effect of JZL184 on [(3)H]AEA uptake support the conclusion that AEA most likely mediates the anti-hyperalgesic effect of JZL184 in this model.
authors.affiliation: Department of Diagnostic and Biological Sciences, Dental School, University of Minnesota, USA.
authors.forename: Iryna A
authors.initials: IA
authors.lastname: Khasabova
authors.affiliation: Department of Diagnostic and Biological Sciences, Dental School, University of Minnesota, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Yao
authors.affiliation: Department of Diagnostic and Biological Sciences, Dental School, University of Minnesota, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Paz
authors.affiliation: College of Biological Sciences, University of Minnesota, USA.
authors.forename: Cutler T
authors.initials: CT
authors.lastname: Lewandowski
authors.affiliation: Pharmacology Graduate Program, University of Minnesota, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Lindberg
authors.affiliation: Department of Neuroscience, Medical School, University of Minnesota, USA.
authors.forename: Lia
authors.initials: L
authors.lastname: Coicou
authors.affiliation: Department of Diagnostic and Biological Sciences, Dental School, University of Minnesota, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Burlakova
authors.affiliation: Department of Diagnostic and Biological Sciences, Dental School, University of Minnesota, USA.
authors.forename: Don A
authors.initials: DA
authors.lastname: Simone
authors.affiliation: Department of Neuroscience, Medical School, University of Minnesota, USA. Electronic address: vseybold@umn.edu.
authors.forename: Virginia S
authors.initials: VS
authors.lastname: Seybold
mesh_terms: D000577:Amides; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D002945:Cisplatin; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism / Q000494:pharmacology; D004983:Ethanolamines / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000494:pharmacology; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D010169:Palmitic Acids / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D000577:Amides; D000700:Analgesics; D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D052117:Benzodioxoles; D063388:Endocannabinoids; D004983:Ethanolamines; D005989:Glycerides; D007211:Indoles; C534333:JZL 184; D009025:Morpholines; D010169:Palmitic Acids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C005958:palmidrol; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; D002945:Cisplatin; C109925:AM 281; C094023:iodopravadoline; C078814:anandamide
keywords: 2-Arachidonoyl-glycerol; Anandamide; Cannabinoid receptor; Cisplatin; Dorsal root ganglion; Hyperlagesia; JZL184; Spinal cord