REGULATION OF DELTA-OPIOID RECEPTORS BY DELTA(9)-TETRAHYDROCANNABINOLIN NG108-15 HYBRID-CELLS

In this study we employed the neuroblastoma x glioma NG 108-15 cell li ne as a model for investigating the effects of long-term activation of cannabinoid receptors on delta opioid receptor desensitization, down- regulation and gene expression. Exposure of NG 108-15 cells to (-)-Del ta(9)-tetrahydrocannabinol (Delta(9)-THC) reduced opioid receptor bind ing, evaluated in intact cells, by approximate to 40 - 45% in cells ex posed for 24 h to 50 and 100 nM Delta(9)-THC and by approximate to 25 % in cells exposed to 10 nM Delta(9)-THC. Lower doses of Delta(9)-THC (0.1 and 1 nM) or a shorter exposure time to the cannabinoid (6 h) wer e not effective. Down-regulation of delta opioid receptors was not obs erved in cells exposed for 24 h to pertussis toxin (PTX) and then trea ted for 24 h with 100 nM Delta(9)-THC. In cells that were exposed for 24 h to the cannabinoid, the ability of Delta(9)-THC and of the delta opioid receptor agonist [D-Ser(2), Leu(5) Thr(6)]enkephalin to inhibit forskolin-stimulated cAMP accumulation was significantly attenuated. Prolonged exposure of NG 108-15 cells to 100 nM Delta(9)-THC produced a significant elevation-of steady-state levels of delta opioid recepto r mRNA. This effect was not observed in cells pretreated with PTX. The selective cannabinoid receptor antagonist SR 141716A blocked the effe cts elicited by Delta(9)-THC on delta opioid receptor desensitization, down-regulation and gene expression; thus indicating that these are m ediated via activation of cannabinoid receptors. These data demonstrat e the existence, in NG 108-15 cells, of a complex cross-talk between t he cannabinoid and opioid receptors on prolonged exposure to Delta(9)- THC triggered by changes in signaling through G(i) and/or G(0)-coupled receptors. (C) 1998 Elsevier Science Inc.