Cannabinoids Regulate δ-Opioid Receptors in NG108-15 Hybrid Cells

We have studied the effects of long-term activation of cannabinoid receptors on opioid receptor desensitization and down-regulation. The mouse neuroblastomaxrat glioma hybridoma NG 108-15 cell line was used as it represents a suitable model expressing both cannabinoid CB1 and δ-opioid receptors linked to Gi proteins. Twenty-four-hour exposure of NG 108-15 cells to the cannabinoid agonist WIN 55, 212-2 mesylate (200 nM) reduced opioid receptor binding, evaluated in intact cells, by approximately 50%. Down-regulation of δ-opioid receptors was not observed in cells exposed to pertussis toxin for 24 h. In cells that were exposed to the cannabinoid for 24 h, the ability of the δ-opioid receptor agonist [D-Ser2, Leu5, Thr6]enkephalin to inhibit forskolin-stimulated cAMP accumulation was significantly attenuated. The selective cannabinoid receptor antagonist SR 141716A blocked the effects elicited by WIN 55,212-2 on δ-opioid receptor desensitization and down-regulation. These data demonstrate the existence, in NG 108-15 cells, of a complex cross-talk between the cannabinoid and opioid receptors.