The Role of Opioid Receptor Phosphorylation and Trafficking in Adaptations to Persistent Opioid Treatment

Abstract

µ-Opioid receptor activation underpins clinical analgesia and is the central event in the abuse of narcotics. Continued opioid use produces tolerance to the acute effects of the drug and adaptations that lead to physical and psychological dependence. Continued µ-receptor signaling provides the engine for these adaptations, with most evidence suggesting that chronic agonist treatment produces only limited alterations in primary µ-opioid receptor signaling. Here we examine agonist regulation of µ-opioid receptor function, and whether this is altered by chronic treatment. Receptor phosphorylation is thought to be the key initial event in agonist regulation of the µ-opioid receptor, providing a signal for acute receptor desensitization and also subsequent receptor resensitization. Morphine appears to produce qualitatively and quantitatively different µ-receptor phosphorylation than other agonists, but the consequences of this remain obscure, at least in neurons. There is no evidence that agonist-induced µ-opioid receptor phosphorylation changes in chronically morphine-treated animals, although receptor regulation appears to be altered. Thus, as receptor phosphorylation and resensitization appear to maintain continued signaling through the µ-opioid receptor, these two events are crucial in facilitating adaptations to chronic opioid treatment, and the possibility that agonist-specific phosphorylation can contribute to the development of different adaptations remains open.

G Protein-coupled Receptor-promoted Trafficking of Gβ1γ2Leads to AKT Activation at Endosomes via a Mechanism Mediated by Gβ1γ2-Rab11a Interaction

“…with ␤-arrestins (Ferguson, 2001;Luttrell and Lefkowitz, 2002;Tohgo et al, 2003;Ahn et al, 2004;Prossnitz, 2004;Johnson et al, 2005;Lefkowitz et al, 2006;Marrari et al, 2007;Moore et al, 2007). The role of internalized heterotrimeric G proteins in vesicular trafficking has been recently recognized in yeast, in which it was demonstrated that endocytosis of G␣ is a required step in the signaling to Vps34, the yeast PI3K (Slessareva et al, 2006).…”

Desensitization and Trafficking of μ-Opioid Receptors in Locus Ceruleus Neurons: Modulation by Kinases

“…It is known, however, that MOPRs are phosphorylated by multiple kinases (Johnson et al, 2005). Several kinase-dependent mechanisms have been proposed to mediate desensitization.…”

Regulation ofµ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance

“…For example, biochemical assays for desensitization, such as inhibition of adenylyl cyclase that requires more than 5 minutes of sustained opioid exposure (most assays take 10-20 minutes, e.g., Law et al, 2000, or longer, e.g., Koch et al, 2005, measure the combined effects of rapid desensitization at the cell surface plus endocytosis or recovery from desensitization. Robust desensitization generally precedes endocytosis and can occur when endocytosis is absent or prevented (Johnson et al, 2005;Arttamangkul et al, 2006;Dang et al, 2009). While it is clear that arrestindependent internalization can sequester the opioid receptors in compartments that reduce the efficiencies of certain forms of signaling (e.g., Gbg activation of Kir3 channels), it is now equally clear that arrestin binding does not inactivate all receptor signaling.…”