title: Inhibition of anandamide hydrolysis attenuates nociceptor sensitization in a murine model of chemotherapy-induced peripheral neuropathy.
abstract: Painful neuropathy frequently develops as a consequence of commonly used chemotherapy agents for cancer treatment and is often a dose-limiting side effect. Currently available analgesic treatments are often ineffective on pain induced by neurotoxicity. Although peripheral administration of cannabinoids, endocannabinoids, and inhibitors of endocannabinoid hydrolysis has been effective in reducing hyperalgesia in models of peripheral neuropathy, including chemotherapy-induced peripheral neuropathy (CIPN), few studies have examined cannabinoid effects on responses of nociceptors in vivo. In this study we determined whether inhibition of fatty acid amide hydrolase (FAAH), which slows the breakdown of the endocannabinoid anandamide (AEA), reduced sensitization of nociceptors produced by chemotherapy. Over the course of a week of daily treatments, mice treated with the platinum-based chemotherapy agent cisplatin developed robust mechanical allodynia that coincided with sensitization of cutaneous C-fiber nociceptors as indicated by the development of spontaneous activity and increased responses to mechanical stimulation. Administration of the FAAH inhibitor URB597 into the receptive field of sensitized C-fiber nociceptors decreased spontaneous activity, increased mechanical response thresholds, and decreased evoked responses to mechanical stimuli. Cotreatment with CB1 (AM281) or CB2 (AM630) receptor antagonists showed that the effect of URB597 was mediated primarily by CB1 receptors. These changes following URB597 were associated with an increase in the endocannabinoid anandamide in the skin. Our results suggest that enhanced signaling in the peripheral endocannabinoid system could be utilized to reduce nociceptor sensitization and pain associated with CIPN.
authors.affiliation: Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Uhelski
authors.affiliation: Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Iryna A
authors.initials: IA
authors.lastname: Khasabova
authors.affiliation: Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, Minnesota simon003@umn.edu.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Simone
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D002945:Cisplatin / Q000009:adverse effects; D063388:Endocannabinoids / Q000378:metabolism*; D006868:Hydrolysis; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D036421:Nerve Fibers, Unmyelinated / Q000378:metabolism / Q000502:physiology; D059225:Nociception; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D012867:Skin / Q000293:injuries; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D063387:Cannabinoid Receptor Antagonists; D002219:Carbamates; D002945:Cisplatin; D063388:Endocannabinoids; D007211:Indoles; D009025:Morpholines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C109925:AM 281; C094023:iodopravadoline; C078814:anandamide
keywords: AM281; AM630; URB597; allodynia; cisplatin; mouse; tibial nerve