Using delta opioid receptor as a model system, acute desensitization of neuronal opioid receptor was studied in detail in neuroblastoma x glioma NG108-15 cells and primarily-cultured mouse cortical cells. The opioid desensitization could occur in as short as 3 minutes of agonist treatment and the half-life of the desensitized state was about 90 minutes. This acute opioid desensitization was homologous in nature in both neuronal cells. The acute desensitization was almost abolished by treatment of the neuronal cells with staurosporine, a nonspecific protein kinase inhibitor. Treatment with the protein kinase C-selective inhibitor, calphostin C, however, caused partial block. In conclusion, neuronal opioid receptor undergoes acute, agonist-dependent, and homologous desensitization, during which protein kinases appear to play an important role.