mu opiate receptors, the principal sites for opiate analgesia and reward, can display compensatory responses to opiate agonist drug administration. Agonist-induced K+ channel responses mediated by these receptors desensitize when examined in Xenopus oocyte expression systems. Mechanisms underlying such processes could include phosphorylation events similar to those reported to desensitize other G-protein-linked receptors. We used C-terminally directed anti-mu receptor antibodies to immunoprecipitate a phosphoprotein with size appropriate for the mu receptor from stably expressing Chinese hamster ovary cells. Phosphorylation of this mu opiate receptor protein was enhanced approximately 5-fold by treatment with the mu agonist morphine. The time course and dose-response relationships between mu receptor phosphorylation and agonist-induced desensitization display interesting parallels. Phosphorylation of mu opiate receptor protein is also enhanced approximately 5-fold by treatment with the protein kinase C activator phorbol 12-myristate 13-acetate. The protein kinase inhibitor staurosporine blocked the effect of phorbol 12-myristate 13-acetate on mu receptor phosphorylation. However, staurosporine failed to block morphine-induced phosphorylation. These observations suggest that several biochemical pathways can lead to mu receptor phosphorylation events that may include mechanisms involved in mu receptor desensitization.