INDEPENDENCE OF, AND INTERACTIONS BETWEEN, CANNABINOID AND OPIOID SIGNAL-TRANSDUCTION PATHWAYS IN N18TG2 CELLS

N18TG2 neuroblastoma cells co-express delta-opioid and CB1-cannabinoid receptors. Both receptors are negatively coupled to adenylyl cyclase through pertussis toxin-sensitive GTP-binding proteins. In the present study, we confirmed the independent activity of opioid and cannabinoi d agonists, and investigated chronic interactions between the two sign al transduction pathways in these cells. Opioid and cannabinoid agonis ts stimulated [S-35]guanosine-5'-O-(3-thiotriphosphate) binding to N18 TG2 membranes. When the opioid agonist etorphine and the cannabinoid a gonist desacetyllevonantradol (DALN) were applied together, the stimul ation was similar to the arithmetic sum of the two separate effects. T his additivity existed even after partial ablation of the G-proteins r eservoir with a low concentration of pertussis toxin, indicating that opioid and cannabinoid receptors activate different pools of G-protein s in N18TG2 cells. Chronic treatment of the cells with either opioid o r cannabinoid agonists induced desensitization to the respective drug. In addition, asymmetric cross-desensitization was found: while long-t erm exposure to DALN induced homologous desensitization, and did not r educe the effect of etorphine, long-term exposure to etorphine attenua ted the cannabinoid activation of G-proteins. Chronic exposure to eith er DALN or etorphine not only induced desensitization, but also elevat ed the basal activity of G-proteins in the exposed cells. The combinat ion of the two drugs did not yield an additive activation, suggesting that chronic exposure of N18TG2 cultures to cannabinoid and opioid ago nists modified a common responding element within the cells. This work presents the N18TG2 neuroblastoma as a suitable experimental model to study the molecular mechanism(s) underlying chronic interactions betw een opioid and cannabinoid drugs. (C) 1998 Elsevier Science B.V. All r ights reserved.