ACTIVATION OF SPINAL CANNABINOID CB_2 RECEPTORS INHIBITS NEUROPATHIC PAIN IN STREPTOZOTOCIN-INDUCED DIABETIC MICE

摘要

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 3 fig, i.t.) dose-depen-dently prolonged the tail-flick latency, whereas there were no changes with the injection of either cannabinoid CB_1 (AM 251,1 mug, i.t.) or CB_2 (AM 630, 4 mug, i.t.) receptor antagonists. AM 251 (1 mug, i.t.), but not AM 630 (4 mug, i.t.), significantly inhibited the prolongation of the tail-flick latency induced by WIN-55,212-2 (3 mug, 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 (1 mug, i.t.) significantly recovered the tail-flick latency in STZ-induced diabetic mice. The effect of WIN-55,212-2 (1 mug, i.t.) in STZ-induced diabetic mice was significantly inhibited by AM 630 (4 mug, i.t.), but not AM 251 (1 mug). The selective cannabinoid CB_2 receptor agonist L-759,656 (19 and 38 mug, i.t.) also dose-dependently recovered the tail-flick latency in STZ-induced diabetic mice, and this recovery was inhibited by AM 630 (4 mug, i.t.). The protein levels of cannabinoid CB_1 receptors, CB_2 receptors and diacylglycerol lipase a (DGL-alpha), the enzyme that synthesizes endocannabinoid 2-arachi-donoylglycerol, in the spinal cord were examined using Western blotting. The protein levels of both cannabinoid CB_1 and CB_2 receptors were increased in STZ-Tnduced diabetic mice, whereas the protein level of DGL-alpha was significantly decreased. These results indicate that spinal cannabinoid systems are changed in diabetic mice and suggest that cannabinoid CB_2 receptor agonists might have an ability to recover diabetic neuropathic pain.