Constitutive Activation of the μ-Opioid Receptor: A Novel Paradigm of Receptor Regulation in Narcotic Analgesia, Tolerance, and Dependence

Abstract
The activity of G-protein-coupled receptors is regulated by phosphorylation, which is generally thought to result in desensitization. In contrast, we propose that the phosphorylated state of the μ-opioid receptor, termed μ*, is constitutively active (i.e., it continues to signal in the absence of any agonist). Exposure to a μ, agonist enhances phosphorylation of the μ receptor by protein kinases. The resultant gradual conversion of μ to μ* could affect the duration of analgesia after administration of narcotic drugs, and it is proposed to play a key role in narcotic tolerance and dependence. We discuss evidence in support of these hypotheses, and implications for the safe use of narcotic analgesics and the treatment of narcotic tolerance and dependence.

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