Mechanism and consequences of delta-opioid receptor internalization.

G protein-coupled delta-opioid receptors (DORs) participate in opioid-mediated analgesia, and chronic opioid application is well known to produce tolerance, limiting the therapeutic use of these drugs. To control and eventually avoid the underlying adaptive mechanisms, several cellular functions were examined with regard to their roles in tolerance development. Specific interest focused on DOR internalization, and the relevant findings are reviewed here. In general, DOR endocytosis is accomplished by complex interactions of various determinants, each having distinct roles in this process. For instance, DOR activation by certain opioids has been shown to turn on the machinery of endocytosis, whereas other opioids stimulate the receptors but fail to bring about internalization. In addition, receptor phosphorylation by different kinases was commonly found to promote DOR sequestration, but receptor internalization also occurs without their phosphorylation. A central role in DOR endocytosis is referred to the adaptor proteins arrestin-2 and arrestin-3, which bind to receptors and subsequently cause the formation of clathrin-coated pits to trigger dynamin-controlled endocytosis. Distinct sorting proteins, kinases, and phosphatases determine whether internalized DORs are delivered either for proteolytic degradation or for recycling, although the underlying mechanisms are hence not clear. Despite intensive studies, understanding of DOR sequestration, degradation, and recycling becomes increasingly difficult. However, the phenomenon of cellular desensitization is recognized to correspond to the loss of responsiveness as consequence of DOR internalization and degradation. In contrast, DOR endocytosis is also discussed to promote resensitization of cells to opioids by recycling of internalized DORs. Even stimulation of extracellular signal-regulated protein kinases (ERK 1/2) may be accomplished by DOR sequestration. However, opposite findings, as well as the fact that multiple cellular mechanisms underly receptor desensitization, resensitization, and ERK activation, questions whether DOR internalization is essential for these processes. Further investigations in both the cellular mechanism and the consequences of DOR endocytosis might thus reveal new aspects of opioid-controlled functions.