Dissertation

The molecular regulation of the mu-opioid receptor

Burd, Amy Lee

1998

Overview

While opioids are still one of the most common analgesics used, they elicit numerous side effects with the most important being the development of tolerance and dependence. By understanding the cellular mechanisms of tolerance, novel approaches to treating pain can be evaluated. Tolerance has been theorized to develop in response to cellular adaptations, including downregulation and desensitization. To date, the mechanisms responsible for desensitization and downregulation and their correlation with tolerance have not been fully evaluated. Phosphorylation of the carboxyl tail of the μ-opioid receptor, however, is believed to initiate these processes. From truncation, deletion, and point mutation studies, the specific amino acids, Ser 356 and Ser363, that mediate etorphine-induced down-regulation of the μ-opioid receptor have been elucidated. Interestingly, Ser 356 and Ser363 are not specifically phosphorylated, however, over-expression of GRK2 or arrestin reverses the observed attenuation. Altogether, these results suggest that phosphorylation of the μ-opioid receptor is not obligatory for etorphine-induced down-regulation. In contradiction, point mutation of the twelve serine and threonine residues to alanine within the carboxyl tail of the μ-opioid receptor has no effect on the rate of desensitization when compared to the wild-type receptor. This lack of correlation suggests that phosphorylation may not have as prominent a role in the regulation of the μ-opioid receptor as with other G-protein-coupled-receptors. In total, this investigation highlights the complexity of the regulation of the μ-opioid receptor and indicates that other constituents are involved in these processes.

• Publisher: ProQuest Dissertations & Theses
• Subject: Molecular biology / Pharmacology
• ISBN: 9780599118515, 0599118512