Unraveling the Mechanisms of Opioid-Induced Airway Constriction: A Path towards Novel Therapeutics for Opioid Overdose - PROJECT SUMMARY This career development award will allow Dr. Nicholas Burgraff to establish an independent research career dedicated to understanding the neurophysiological control of airway function and its intricate interactions within neural networks that regulate respiration, with a pivotal focus on how various pharmaceuticals, notably opioids, can disrupt these systems. This line of research is crucial as it addresses how drugs may inadvertently contribute to potentially life-threatening complications like respiratory depression. The training plan and research strategy outlined in this proposal, combined with Dr. Burgraff's experience in translational physiology, respiration, and rhythm generation, positions him exceptionally well for success in this endeavor. The primary sites of focus in this research are the Dorsal Motor Nucleus of the Vagus, Nucleus Tractus Solitarius, and Nucleus Ambiguus, areas with significant influences on airway smooth muscle control and the balance of autonomic regulation. We hypothesize that fentanyl disrupts this balance, favoring parasympathetic dominance that leads to airway constriction. Additionally, the study aims to establish dual-action treatments targeting both this constriction and rhythm disruptions without reversing opioid binding, offering a new paradigm in opioid overdose interventions. This project will expand Dr. Burgraff’s prior training in electrophysiology and whole animal physiology by incorporating cutting-edge techniques including retrograde viral tracing, immunohistochemistry, optogenetics, and high-density neural recordings. Merging these methodologies will allow Dr. Burgraff to leverage a multi-level approach to investigate the functional dynamics of fentanyl on neuronal circuits controlling airway constriction and assess counteractive strategies. Building upon Dr. Burgraff's preliminary results, the proposed research will pave the way for developing effective therapeutic strategies that complement or replace conventional opioid reversal strategies. By shedding light on the specific neural circuits and autonomic mechanisms underlying fentanyl-induced airway constriction, this project holds the potential to significantly improve patient safety and outcomes in various medical scenarios where opioids are used, from acute pain to long-term opioid therapy. This investigation thus aligns seamlessly with Dr. Burgraff's career objectives, his pursuit of R01 funding, and his commitment to advancing the understanding and management of complications associated with opioid use. To assist Dr. Burgraff in accomplishing the research and career development objectives of this proposal, he will receive strong mentorship from Dr. Nino Ramirez, a distinguished figure in respiratory rhythm generation with an impressive track record in mentorship. He will also be supported by an advisory committee of established professors and attending physicians, all with expertise in the techniques and translational relevancies that are integral to this proposal. With full institutional support and the additional training, mentorship, and experience that this grant will provide, Dr. Burgraff will be positioned to successfully compete for R01-funding and establish a high-impact independent research program in this critical area of study.
