Activation of Cannabinoid CB2Receptors Suppresses C-Fiber Responses and Windup in Spinal Wide Dynamic Range Neurons in the Absence and Presence of Inflammation

Abstract

Effects of the CB2-selective cannabinoid agonist AM1241 on activity evoked in spinal wide dynamic range (WDR) neurons by transcutaneous electrical stimulation were evaluated in urethane-anesthetized rats. Recordings were obtained in both the absence and the presence of carrageenan inflammation. AM1241, administered intravenously or locally in the paw, suppressed activity evoked by transcutaneous electrical stimulation during the development of inflammation. Decreases in WDR responses resulted from a suppression of C-fiber–mediated activity and windup. Aβ- and Aδ-fiber–mediated responses were not reliably altered. The AM1241-induced suppression of electrically evoked responses was blocked by the CB2antagonist SR144528 but not by the CB1antagonist SR141716A. AM1241 (33 μg/kg intraplantar [ipl]), administered to the carrageenan-injected paw, suppressed activity evoked in WDR neurons relative to groups receiving vehicle in the same paw or AM1241 in the opposite (noninflamed) paw. The electrophysiological effects of AM1241 (330 μg/kg intravenous [iv]) were greater in rats receiving ipl carrageenan compared with noninflamed rats receiving an ipl injection of vehicle. AM1241 failed to alter the activity of purely nonnociceptive neurons recorded in the lumbar dorsal horn. Additionally, AM1241 (330 μg/kg iv and ipl; 33 μg/kg ipl) reduced the diameter of the carrageenan-injected paw. The AM1241-induced decrease in peripheral edema was blocked by the CB2but not by the CB1antagonist. These data demonstrate that activation of cannabinoid CB2receptors is sufficient to suppress neuronal activity at central levels of processing in the spinal dorsal horn. Our findings are consistent with the ability of AM1241 to normalize nociceptive thresholds and produce antinociception in inflammatory pain states.