Activation of spinal cannabinoid CB₂ receptors inhibits neuropathic pain in streptozotocin-induced diabetic mice

The role of spinal cannabinoid systems in neuropathic pain of streptozotocin (STZ)-induced diabetic mice was studied. In normal mice, injection of the cannabinoid receptor agonist WIN-55,212-2 (1 and 3μg, i.t.) dose-dependently prolonged the tail-flick latency, whereas there were no changes with the injection of either cannabinoid CB₁ (AM 251, 1μg, i.t.) or CB₂ (AM 630, 4μg, i.t.) receptor antagonists. AM 251 (1μg, i.t.), but not AM 630 (4μg, i.t.), significantly inhibited the prolongation of the tail-flick latency induced by WIN-55,212-2 (3μg, i.t.). In STZ-induced diabetic mice, the tail-flick latency was significantly shorter than that in normal mice. A low dose of WIN-55,212-2 (1μg, i.t.) significantly recovered the tail-flick latency in STZ-induced diabetic mice. The effect of WIN-55,212-2 (1μg, i.t.) in STZ-induced diabetic mice was significantly inhibited by AM 630 (4μg, i.t.), but not AM 251 (1μg). The selective cannabinoid CB₂ receptor agonist L-759,656 (19 and 38μg, i.t.) also dose-dependently recovered the tail-flick latency in STZ-induced diabetic mice, and this recovery was inhibited by AM 630 (4μg, i.t.). The protein levels of cannabinoid CB₁ receptors, CB₂ receptors and diacylglycerol lipase α (DGL-α), the enzyme that synthesizes endocannabinoid 2-arachidonoylglycerol, in the spinal cord were examined using Western blotting. The protein levels of both cannabinoid CB₁ and CB₂ receptors were increased in STZ-induced diabetic mice, whereas the protein level of DGL-α was significantly decreased. These results indicate that spinal cannabinoid systems are changed in diabetic mice and suggest that cannabinoid CB₂ receptor agonists might have an ability to recover diabetic neuropathic pain.