Figure 7.

Arrestins are recruited in a ligand-specific manner to the delta opioid receptor. Under basal conditions (no agonist bound), delta opioid receptors are in a pre-engaged complex with arrestin 3 at the cell membrane. High-internalizing agonist such as SNC80 induce substantial receptor phosphorylation, preferentially recruit arrestin 2, and result in receptor internalization and degradation. In contrast, low-internalizing agonists such as ARM390 and JNJ20788560 induce a receptor confirmation that strengthens the engagement between delta opioid receptor and arrestin 3 at the cell membrane and encourages receptor resensitization, thus preventing acute behavioral tolerance. In the absence of arrestin 3, low-internalizing agonists undergo desensitization similarly to WT animals, but we hypothesize that a different receptor complex is formed, perhaps with arrestin 2 or another GPCR modulator, which hinders resensitization. The mechanism underlying arrestin 3-mediated receptor resensitization remains to be elucidated.