Joseph Watso - US grants

PROJECT SUMMARY/ABSTRACT National Institutes of Health Director Francis Collins, MD, PhD and drug abuse expert Nora Volkow, MD recently stated that we need to prioritize ?finding safe and effective interventions to manage chronic pain? and that we must ?find new, innovative medications?to treat opioid addiction.? Low dose ketamine, a N-methyl-D-aspartate antagonist, effectively reduces pain in pre-hospital and hospital settings and reduces opioid use in acute pain settings. Recent clinical trials have demonstrated that low dose ketamine reduces psychiatric symptoms associated with major depressive disorders, anxiety disorders, alcohol withdrawal syndrome, and chronic migraine. However, future clinical applications of low dose ketamine are currently limited due to well-founded cardiovascular safety concerns. Thus, the poorly understood cardiovascular safety profile of low dose ketamine remains a critical barrier, potentially limiting its future therapeutic usage. Specifically, ketamine elicits hypertensive episodes that sometimes require immediate pharmacological treatment, and can last for several hours, even in healthy non-hypertensive adults. Currently, we are only partially informed of the mechanisms underlying these adverse effects through reports in anesthetized animals, which suggest that sympathetic nervous system overactivity and impaired cardiovascular function contribute to ketamine-induced elevations in blood pressure. Therefore, the primary objective of this proposed work is to determine the contribution of the autonomic nervous system and vasculature that cause prolonged hypertensive responses to low dose ketamine using direct in vivo assessment of sympathetic nervous system activity. We proposed a randomized, double- blind, crossover, placebo-controlled trial in which each participant will complete ketamine and placebo experimental trials. During each visit we will assess neural and cardiovascular function following the ketamine (or placebo) administration. The proposed work will, for the first time, comprehensively examine the mechanisms by which low dose ketamine causes hypertensive episodes in healthy humans. The results generated from this project will contribute fundamental knowledge about the cardiovascular safety profile of low dose ketamine in humans. This research directly supports the mission of NHLBI in that we will uncover and translate mechanistic physiological findings from human participants with the goal of translating these findings to guide future clinical practice. To ensure that this study was designed to maximize clinical relevance and my scientific training, I assembled a strong interdisciplinary clinical research team consisting of expert cardiovascular physiologists Craig Crandall, PhD, and Paul Fadel, PhD, anesthesiologist Joseph Hendrix, MD, clinician-scientists Benjamin Levine, MD, Satyam Sarma, MD, David Goldstein, MD, PhD, and Arthur Westover, MD. My primary goals during this fellowship are to complete the proposed project, master several technical skills (e.g. ultrasound-guided radial microneurography, cardiac echocardiography), improve my ability to obtain future extramural research funding (e.g., a NHLBI K99/R00), and publish research findings in peer-reviewed medical and physiology journals.