Cellular tolerance at the μ-opioid receptor is phosphorylation dependent

The role of phosphorylation of the μ-opioid receptor (MOR) in desensitization, internalization and long-term tolerance was examined in locus coeruleus (LC) neurons. Viral expression of wild type (exWT) and mutant MORs, where all phosphorylation sites on the C-terminus (Total Phosphorylation Deficient (TPD)) were mutated to alanine, were examined in a MOR knockout rat. Both expressed receptors acutely activate potassium conductance similar to endogenous receptors in wild type animals. The exWT receptors, like endogenous receptors, displayed signs of tolerance after chronic morphine treatment. There was however a loss of agonist-induced desensitization and internalization in experiments with the TPD receptors. In addition the development of tolerance was not observed in the TPD receptors following chronic morphine treatment. The results indicate a key role of C-terminal phosphorylation in the expression of acute desensitization, trafficking and long-term tolerance to morphine.