ACTIVATION OF N-METHYL-D-ASPARTATE RECEPTOR ATTENUATES ACUTE RESPONSIVENESS OF DELTA-OPIOID RECEPTORS

Coadministration of antagonists of N-methyl-D-aspartate (NMDA) recepto r and opioids has been shown to prevent development of opiate toleranc e in animal and clinical studies, but its cellular and molecular mecha nisms are not understood. In this study, the effect of NMDA on delta-o pioid receptor (DOR)mediated signal transduction was investigated in n euroblastoma x glioma NG108-15 cells that functionally express both DO R and NMDA receptors. Acute incubation of NG108-15 cells with NMDA, a specific agonist of NMDA receptor, significantly attenuated the abilit y of DOR agonist [D-Pen(2), D-Pen(5)]enkephalin (DPDPE) to inhibit for skolin-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 delta-opioid receptors to DPDPE could be blocked by ketamine, a NMDA r eceptor-specific antagonist. This NMDA attenuation effect on DOR activ ity was also obsewed in neuronal primary cell cultures from fetal mous e brain but not in the Chinese hamster ovary cell line stably transfec ted with DOR alone. Interestingly, NMDA pretreatment reduced the cellu lar response to epinephrine but not to that of prostaglandin E-1 in NG 108-15 cells, which suggests differential modulation of NMDA on differ ent G protein-coupled receptors. Pretreatment of NG108-15 cells with k etamine along with DPDPE greatly attenuated DPDPE-induced acute desens itization of DOR. Furthermore. the specific inhibitors of protein kina se C, either chelerythrine chloride or Go 6979, effectively blocked th e NMDA effect, which indicates the involvement of protein kinase C in the process. In conclusion, the activation of NMDA receptors can atten uate acute responsiveness of DOR in neuronal cells, whereas its blocka ge leads to reduction of DOR desensitization. These results have thus provided an insight into cross-talk between NMDA and opioid signal tra nsduction.