A peripheral cannabinoid CB2 mechanism modulates the activity of spinal wide dynamic range neurons in a rat model of inflammation
Nackley, Andrea Gail
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Activation of cannabinoid CB2 receptors attenuates nociception in models of acute and chronic pain, while failing to produce centrally-mediated effects such as hypothermia and catalepsy. The present study was conducted to test the hypothesis that activation of peripheral CB2 receptors suppresses the development of inflammationevoked excitability of wide dynamic range (WDR) neurons in the spinal dorsal horn. Intraplantar carrageenan increased the responsiveness of WDR neurons to trains of electrical stimuli applied to the cutaneous receptive field of isolated neurons. The CB2 selective cannabinoid agonist AM1241 (330 mg/kg) attenuated the development of carrageenan-evoked neuronal excitability when administered intravenously or locally in the paw. Decreases in WDR neuron responses resulted from a suppression of C-fibermediated activity. Ab- and Ad-fiber-mediated responses were not reliably altered during any experiment. Pharmacological specificity was evaluated in studies employing intravenous drug administration. The AM1241-induced suppression of carrageenanevoked increased neuronal sensitization was blocked by the CB2 antagonist SR144528 but not by the CB1 antagonist SR141716A. Intraplantar administration of AM1241 (33 mg/kg) suppressed the excitability of WDR neurons following administration to the carrageenan-injected paw but was inactive following administration in the contralateral (noninflamed) paw, consistent with a local site of action. Additionally, AM1241 (330 mg/kg, iv and ipl; 33 mg/kg ipl) reduced hindpaw diameter in the carrageenan -injected paw. The AM1241-induced decrease in hindpaw diameter was blocked by the CB2 but not the CB1 antagonist. These data provide evidence that actions at cannabinoid CB2 receptors are sufficient to suppress inflammation-evoked neuronal activity at rostral 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.