Proposed model for effect of MOR/GPR177interaction on Wnt secretion. (A) Under basal conditions, MOR and GPR177 are associated at the plasma membrane (PM) and in recycling vesicles (V). However, GPR177 is located primarily in vesicles in association with Wnts, whereas MOR is predominantly plasma membrane-associated. Recycling of GPR177 from PM to Golgi (G) is mediated via retromer, and is required for Wnt secretion. (B) In the presence of morphine, MORs are inefficiently internalized which leads to an increase in the association between MOR and GPR177 near the plasma membrane. This results in reduced retromer-mediated GPR177 recycling and functional sequestration of GPR177 activity. Reduced recycling of GPR177 leads to inhibition of Wnt secretion. (C) In the presence of DAMGO, MORs are efficiently internalized which allows for internalization of GPR177 proteins associated with MORs. Once internalized, GPR177 is recycled to the Golgi apparatus via retromer, thereby allowing GPR177 to associate with Wnt proteins and functionally support Wnt protein secretion.