Identifying Genetic Regulators of Opioid Signaling Bias

PROJECT SUMMARY / ABSTRACT Opioids are the most widely used and effective agents for treating pain but are highly addictive. In addition, side effects such as nausea and respiratory depression often accompany their use, making opioids undesired by many prescribers and patients. That said, their unmatched ability to manage pain has led to continued administration and use, viewed as a necessary evil. Opioid actions, both good and bad, primarily originate at the µ opioid receptor (MOR), a G protein-coupled receptor (GPCR) found throughout the central nervous system. By activating MOR, opioids initiate various intracellular signaling pathways that mediate distinct responses. The divergence of opioid actions along these pathways are believed to be the source of co-occurring analgesic and adverse effects. In addition, the dynamic balance between pathways has implicated roles in opioid tolerance and addiction. Towards the goal of making opioid treatment safe and effective, it is essential to understand how regulation occurs along these pathways and how dysregulated systems impact signaling biases. Here, my studies will address this by identifying new regulators and determining how they influence MOR biology. Using a set of ~ 80 pre-validated genetic candidates, I will implement a MOR-MAPK platform to identify the most impactful MAPK regulators. My preliminary experiments already validated this approach and revealed several new MOR regulators. In line with these exciting new findings, mechanistic details of how this new element affects MOR signaling will be explored and followed up by studies exploring its impact on processing opioid signals in native neurons. Taken together, this will expand our understanding of the opioid signaling landscape and may provide new genetic targets for tuning signaling biases towards safe and effective opioid treatments.