Agonist-specific regulation of delta-opioid receptor trafficking by G protein-coupled receptor kinase and beta-arrestin

Opioid receptors mediate multiple biological functions through their intera ction with endogenous opioid peptides as well as opioid alkaloids including morphine and etorphine. Previously we have reported that the ability of di stinct opioid agonists to differentially regulate CL-opioid receptor (mu OR ) responsiveness is related to their ability to promote G protein-coupled r eceptor kinase (GRK)-dependent phosphorylation of the receptor (1). In the present study, we further examined the role of GRK and p-arrestin in agonis t-specific regulation of the delta-opioid receptor (delta OR). While both e torphine and morphine effectively activate the SBR, only etorphine triggers robust delta OR phosphorylation followed by plasma membrane translocation of beta-arrestin and receptor internalization. In contrast, morphine is una ble to either elicit FOR phosphorylation or stimulate beta-arrestin translo cation, correlating with its inability to cause FOR internalization. Unlike for the mu OR, overexpression of GRK2 results in neither the enhancement o f delta OR sequestration nor the rescue of FOR-mediated p-arrestin transloc ation. Therefore, our findings not only point to the existence of marked di fferences in the ability of different opioid agonists to promote delta OR p hosphorylation by GRK and binding to beta-arrestin, but also demonstrate di fferences in the regulation of two opioid receptor subtypes. These observat ions may have important implications for our understanding of the distinct ability of various opioids in inducing opioid tolerance and addiction.