Opioid overdose deaths remain a major public health problem in the US. It is now recognized that surgery and post-operative pain are major contributors to persistent opioid use and dependence. Inadequate management of intraoperative nociception can lead to increased post-operative pain, which can lead to increased opioid utilization, chronic pain, opioid dependence, and opioid abuse. In this perioperative setting a major challenge is that patients are either unconscious (in the operating room) or heavily sedated (in the post-anesthesia care unit) and cannot report their pain levels. In these scenarios, anesthesiologists and nurses can only guess the opioid requirements for their patients, as they have no means to measure opioid drug effects in real-time. A real-time measurement of opioid drug effects, if it existed, would allow anesthesiologists and nurses to precisely titrate opioids and could significantly improve post-operative pain management and subsequent rates of opioid utilization, dependence, and overdose. Over the past two years my laboratory has developed a real- time biomarker for opioid drugs that could be used to provide more precise titration of opioid drugs and for drug discovery applications. In this project we propose to investigate the mechanisms underlying this biomarker and develop further translational science to support clinical application of this biomarker.