RT Journal Article SR Electronic T1 Activation of N-Methyl-d-Aspartate Receptor Attenuates Acute Responsiveness of δ-Opioid Receptors JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 583 OP 587 DO 10.1124/mol.51.4.583 VO 51 IS 4 A1 Ying-Chun Cai A1 Lan Ma A1 Guo-Huang Fan A1 Jing Zhao A1 Li-Zhen Jiang A1 Gang Pei YR 1997 UL http://molpharm.aspetjournals.org/content/51/4/583.abstract AB Coadministration of antagonists ofN-methyl-d-aspartate (NMDA) receptor and opioids has been shown to prevent development of opiate tolerance in animal and clinical studies, but its cellular and molecular mechanisms are not understood. In this study, the effect of NMDA on δ-opioid receptor (DOR)-mediated signal transduction was investigated in neuroblastoma × glioma NG108–15 cells that functionally express both DOR and NMDA receptors. Acute incubation of NG108–15 cells with NMDA, a specific agonist of NMDA receptor, significantly attenuated the ability of DOR agonist [d-Pen2,d-Pen5]-enkephalin (DPDPE) to inhibit forskolin-stimulated cAMP production. The attenuation caused by NMDA was dose-dependent, and the EC50 of DPDPE increased 100-fold (from 4.6 nm to 500 nm) after NMDA treatment. The NMDA effect on responsiveness of δ-opioid receptors to DPDPE could be blocked by ketamine, a NMDA receptor-specific antagonist. This NMDA attenuation effect on DOR activity was also observed in neuronal primary cell cultures from fetal mouse brain but not in the Chinese hamster ovary cell line stably transfected with DOR alone. Interestingly, NMDA pretreatment reduced the cellular response to epinephrine but not to that of prostaglandin E1 in NG108–15 cells, which suggests differential modulation of NMDA on different G protein-coupled receptors. Pretreatment of NG108–15 cells with ketamine along with DPDPE greatly attenuated DPDPE-induced acute desensitization of DOR. Furthermore, the specific inhibitors of protein kinase C, either chelerythrine chloride or Gö 6979, effectively blocked the NMDA effect, which indicates the involvement of protein kinase C in the process. In conclusion, the activation of NMDA receptors can attenuate acute responsiveness of DOR in neuronal cells, whereas its blockage leads to reduction of DOR desensitization. These results have thus provided an insight into cross-talk between NMDA and opioid signal transduction.