The Involvement of the Endocannabinoid System in the Peripheral Antinociceptive Action of Ketamine.

Ketamine 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. PERSPECTIVE: This study suggests that ketamine antinociception depends at least in part on AEA release and CB1 cannabinoid receptor activation in inflammatory conditions. This study could potentially help clinicians in the use of ketamine as a peripheral analgesic for inflammatory pain.