Differential Response to Morphine of the Oligomeric State of μ-Opioid in the Presence of δ-Opioid Receptors

Prolonged morphine treatment induces extensive desensitization of the p-opioid receptor (mu OR) which is the G-protein-coupled receptor that primarily mediates the cellular response to morphine. To date, the molecular mechanism underlying this process is unknown. Here, we have used live cell fluorescence imaging to investigate whether prolonged morphine treatment affects the physical environment of mu OR, or its coupling with G-proteins, in two neuronal cell lines. We find that chronic morphine treatment does not change the amount of enhanced yellow fluorescence protein (eYFP)-tagged mu OR on the plasma membrane, and only slightly decreases its association with G-protein subunits. Additionally, morphine treatment does not have a detectable effect on the diffusion coefficient of eYFP-mu OR. However, in the presence of another family member, the delta-opioid receptor (delta OR), prolonged morphine exposure results in a significant increase in the diffusion rate of mu OR Number and brightness measurements suggest that mu OR exists primarily as a dimer that will oligomerize with delta OR into tetramers, and morphine promotes the dissociation of these tetramers. To provide a plausible structural context to these data, we used homology modeling techniques to generate putative configurations of mu OR-delta OR tetramers. Overall, our studies provide a possible rationale for morphine sensitivity.