• Ferreira Renata C M RCM Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil., Marina G M Castor, Fabiana Piscitelli, Vincenzo Di Marzo, Duarte Igor D G IDG Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil., and Romero Thiago R L TRL Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. Electronic a.
• Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
• J Pain. 2018 May 1; 19 (5): 487-495.

AbstractKetamine has been widely used as an analgesic and produces dissociative anesthetic effects. The antinociceptive effects of ketamine have been studied, but the involvement of endocannabinoids in these effects has not yet been investigated. In this study, we evaluated the involvement of the endocannabinoid system in the peripheral antinociceptive effects induced by ketamine. All drugs were administered via the intraplantar route. To induce hyperalgesia, rat paws were injected with prostaglandin E2 (2 µg per paw). The nociceptive threshold for mechanical stimulation was measured in the right hind paw of Wistar rats using the Randall-Selitto test. The tissue levels of anandamide (AEA), 2-arachidonoylglycerol, palmitoylethanolamide, and oleoylethanolamide were measured using liquid chromatography coupled to single quadrupole mass spectrometry. The administration of the cannabinoid receptor type 1 (CB1) antagonist, N(piperidine-1yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl 1 pyrazolcarboxamide (20, 40, and 80 µg per paw), but not the cannabinoid receptor type 2 antagonist, 6-iodo-2-methyl-1-(2-morpholinoethyl)-1H-indol-3-yl) (4-methoxyphenyl) methanone (100 µg per paw), antagonized the ketamine-induced peripheral antinociception in a dose-dependent manner. Additionally, the administration of the endocannabinoid metabolizing enzyme inhibitor (.5 µg per paw) or an AEA reuptake inhibitor, (5Z,8Z,11Z,14Z)N(4Hydroxy2methylphenyl)5,8,11,14 eicosatetraenamide (2.5 µg per paw) significantly enhanced low-dose ketamine-induced peripheral antinociception. AEA paw levels were increased only after ketamine administration to prostaglandin E2-injected paws. These data suggest that ketamine, in the presence of a nociceptive stimulus, induces a selective release of AEA levels and subsequent CB1 cannabinoid activation at the peripheral level.Copyright © 2017 The American Pain Society. Published by Elsevier Inc. All rights reserved.

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