MU OPIOID RECEPTOR--PHOSPHORYLATION AND DESENSITIZATION

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DESCRIPTION: (Applicant's Abstract) The overall goal of the proposed research is to understand the molecular mechanisms of opiate receptors' function, especially the mechanisms underlying the addictive effect of opiate drugs. A prominent characteristic of morphine-like drugs is their ability to induce tolerance and dependence in humans. Receptor desensitization is one of the cellular mechanisms that could play a significant role in these neuroadaptive processes. Agonist-dependent phosphorylation contributes to the mechanisms of desensitization in a wide variety of G-protein linked neurotransmitter receptors. It is hypothesized that phosphorylation plays a role in rapid attenuation of opiate receptor-mediated signal transduction in response to opiate drugs. Receptor phosphorylation also contributes to longer term desensitization events including those that may be involved in tolerance and dependence. To test this hypothesis, a study on the phosphorylation of cloned mu opiate receptor as well as endogenous mu opiate receptors and its functional consequences is proposed. The specific aims of this study are: (1) to characterize mu receptor phosphorylation in neuronal tissues of the rat brain, (2) to define the molecular structures of the receptor that are required for receptor phosphorylation, and (3) to examine the roles of mu receptor phosphorylation in functional regulation of the receptor. This work will provide valuable information of molecular and cellular mechanisms on the functional regulation of the opiate receptors. It should have an impact on our knowledge to the molecular mechanism of drug tolerance, dependence and addiction. Such understanding is fundamental to the pharmacological segregation of the analgesic and additive effects of opiate drugs. An understanding of these mechanisms will hopefully result in rational therapy for treatment and prevention of drug abuse.