title: Therapeutic potential of inhibitors of endocannabinoid degradation for the treatment of stress-related hyperalgesia in an animal model of chronic pain.
abstract: The occurrence of chronic stress, depression, and anxiety can increase nociception in humans and may facilitate the transition from localized to chronic widespread pain. The mechanisms underlying chronic widespread pain are still unknown, hindering the development of effective pharmacological therapies. Here, we exposed C57BL/6J mice to chronic unpredictable stress (CUS) to investigate how persistent stress affects nociception. Next, mice were treated with multiple intramuscular nerve growth factor (NGF) injections, which induced chronic widespread nociception. Thus, combination of CUS and NGF served as a model where psychophysiological impairment coexists with long-lasting hyperalgesia. We found that CUS increased anxiety- and depression-like behavior and enhanced basal nociception in mice. When co-applied with repeated NGF injections, CUS elicited a sustained long-lasting widespread hyperalgesia. In order to evaluate a potential therapeutic strategy for the treatment of chronic pain associated with stress, we hypothesized that the endocannabinoid system (ECS) may represent a target signaling system. We found that URB597, an inhibitor of the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH), and JZL184, an inhibitor of the 2-arachidonoyl glycerol-degrading enzyme monoacylglycerol lipase (MAGL), increased eCB levels in the brain and periphery and were both effective in reducing CUS-induced anxiety measured by the light-dark test and CUS-induced thermal hyperalgesia. Remarkably, the long-lasting widespread hyperalgesia induced by combining CUS and NGF was effectively reduced by URB597, but not by JZL184. Simultaneous inhibition of FAAH and MAGL did not improve the overall therapeutic response. Therefore, our findings indicate that enhancement of anandamide signaling with URB597 is a promising pharmacological approach for the alleviation of chronic widespread nociception in stress-exposed mice, and thus, it could represent a potential treatment strategy for chronic pain associated with neuropsychiatric disorders in humans.
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Ermelinda
authors.initials: E
authors.lastname: Lomazzo
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Bindila
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Floor
authors.initials: F
authors.lastname: Remmers
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Raissa
authors.initials: R
authors.lastname: Lerner
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schwitter
authors.affiliation: Department of Neurophysiology, CBTM, Medical Faculty Mannheim, Heidelberg University, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hoheisel
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology; D001549:Benzamides / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology*; D059350:Chronic Pain / Q000188:drug therapy* / Q000503:physiopathology; D003863:Depression / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020932:Nerve Growth Factor; D010880:Piperidines / Q000494:pharmacology*; D013315:Stress, Psychological / Q000188:drug therapy* / Q000503:physiopathology; D035501:Uncertainty; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D018712:Analgesics, Non-Narcotic; D001549:Benzamides; D052117:Benzodioxoles; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D020932:Nerve Growth Factor; D010880:Piperidines; D000099252:Fatty Acid Amide Hydrolases; C534333:JZL 184; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
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