Modulation of mu-opioid receptor dynamics at the plasma membrane and its implications for signalling and trafficking

The mu opioid receptor (MOP) is the target of most commonly used analgesics, such as morphine. Unfortunately, despite opioids being very effective at treating severe pain, they still induce adverse effects that limit their clinical use, including addiction, respiratory depression and constipation. Indeed, misuse of prescription and illicit opioids is the main cause of the dramatic increase in the number of deaths due to overdose caused by respiratory distress, the so-called “opioid epidemic”. This illustrates that, despite decades of research, there is a pressing need for a better understanding of opioid receptor signalling and regulation. This project builds from prior observations from our lab that start to delineate the mechanisms that regulate MOP signalling in response to different ligands. These mechanisms include translocation of the receptor within the plasma membrane, its phosphorylation and its dynamic interactions with intracellular proteins such as arrestins and protein kinase C (PKC). This project will use a wide range of advanced imaging (Fluorescence correlation spectroscopy, super resolution microscopy) and biophysical techniques (FRET and BRET) combined with classical pharmacology, cell biology and biochemistry approaches to provide further understanding on MOP dynamics and signalling and inform drug development towards the generation of more effective analgesics.