Figure 1.

Previous models to explain how strongly internalizing opioid agonists can proiduc less tolerance than weakly internalizing agonists. (A) Strongly internalizing agonists induce rapid desenisitization of MOR coupling. GRK2-mediated phosphorylation is pivotal for βarr-2 binding and endocytosis, both process that were considered ireversible at the cell surface, so MOR slowly resensitizes over the time course of endocytosis and recycling. (B) With weakly internalizing agonists, MOR desensitizes slowly (accelerated by PKC activity) but accumulates in a phosphorylated desensitized state at the cell surface because it stimulates GRK2 and βarr-2 binding very weakly, so cannot resensitize causing tolerance. As discussed in the text, the crucial assumption that endocytosis (and recycling) is necessary for resensitization is incorrect.