mu-Opioid receptors (MORs) are
G-protein-coupled receptors (GPCRs) that mediate the physiological effects of endogenous
opioid neuropeptides and
opiate drugs such as
morphine. MORs are coexpressed with
neurokinin 1 receptors (NK1Rs) in several regions of the CNS that control
opioid dependence and reward. NK1R activation affects
opioid reward specifically, however, and the cellular basis for this specificity is unknown. We found that
ligand-induced activation of NK1Rs produces a cell-autonomous and nonreciprocal inhibition of MOR endocytosis induced by diverse
opioids. Studies using
epitope-tagged receptors expressed in cultured striatal neurons and a
neuroblastoma cell model indicated that this heterologous regulation is mediated by NK1R-dependent sequestration of
arrestins on endosome membranes. First, endocytic inhibition mediated by wild-type NK1Rs was overcome in cells overexpressing beta-arrestin2, a major
arrestin isoform expressed in striatum. Second, NK1R activation promoted sequestration of beta-arrestin2 on endosomes, whereas MOR activation did not. Third, heterologous inhibition of MOR endocytosis was prevented by mutational disruption of beta-arrestin2 sequestration by NK1Rs. NK1R-mediated regulation of MOR trafficking was associated with reduced
opioid-induced desensitization of
adenylyl cyclase signaling in striatal neurons. Furthermore, heterologous regulation of MOR trafficking was observed in both amygdala and locus ceruleus neurons that naturally coexpress these receptors. These results identify a cell-autonomous mechanism that may underlie the highly specific effects of NK1R on
opioid signaling and suggest, more generally, that receptor-specific trafficking of
arrestins may represent a fundamental mechanism for coordinating distinct GPCR-mediated signals at the level of individual CNS neurons.