2026/03/26 by Ken Solt · 1 voice
Engineering · Physics and Astronomy · #Advanced Sensor and Energy Harvesting Materials #Micro and Nano Robotics #Soft Robotics and Applications
paper · doi:10.1097/01.asm.0001191960.98060.7c
openalex publication_date 2026/03/26 · openalex created_date 2026/03/27 · openalex updated_date 2026/07/23
I remember the moment when my mentor and I celebrated the news that my FAER Mentored Research Training Grant (MRTG) had been funded. I never could have imagined that nearly 20 years later, I would have the honor of presenting the FAER-Helrich Research Lecture at the ASA's annual ANESTHESIOLOGY meeting. The occasion provided a wonderful opportunity to reflect upon my journey as a physician-scientist.Dr. Ken Solt in his lab at the Massachusetts General Hospital in 2006, conducting research for his FAER Mentored Research Training Grant titled “Modulation of 5-HT3A Receptor Kinetics by Inhaled Anesthetics.”As a medical student at the University of Pennsylvania in the 1990s, I was surprised to learn that we didn't know how general anesthetics produce their profound effects on the central nervous system. However, a decade earlier it was established that anesthetics act by binding to proteins rather than lipids, leading to a paradigm shift in anesthetic mechanisms research. I began my research journey studying how anesthetics bind to proteins in the laboratory of Drs. Jonas Johansson and Roderic Eckenhoff. Their encouragement and support inspired me to pursue a career as a physician-scientist. As a resident at Massachusetts General Hospital, I became interested in studying anesthetic effects on neuronal receptors. I pursued a six-month research fellowship as a CA-3 resident in the laboratory of Douglas Raines, MD, where I learned the basics of anesthetic pharmacology and cellular electrophysiology. As a junior faculty member, I continued to work with Dr. Raines and underwent additional training with my FAER grant to study the effects of general anesthetics on serotonin and GABAA receptors. At the conclusion of my MRTG, my interest in anesthetic mechanisms led me to consider an important unmet need in our specialty: the lack of anesthetic reversal agents. When a practitioner is faced with a “cannot intubate, cannot oxygenate” scenario during a routine propofol induction, it would be beneficial – perhaps even lifesaving – to have a reversal agent for propofol. In addition, there are clinical situations when it would be useful to rapidly reverse anesthetic-induced unconsciousness, assisting in the differential diagnosis and treatment of delayed emergence from general anesthesia. There are several classes of drugs with readily available reversal agents, including neuromuscular blockers, opioids, benzodiazepines, and anticoagulants. Unlike general anesthetics, these drugs have well-defined molecular targets and mechanisms of action. Although reversal agents for general anesthetics would be useful, they have been difficult to develop because general anesthetics modulate many molecular targets in the central nervous system. These include GABA, glutamate, acetylcholine, and serotonin receptors, as well as potassium and HCN channels, just to name a few. Therefore, it has been virtually impossible to reverse the effects of general anesthetics by employing the traditional pharmacological approach of receptor antagonism.Dr. Ken Solt presenting the FAER-Helrich Research Lecture titled “Activating the Brain's Arousal Systems to Reverse Drug-induced Unconsciousness” at ANESTHESIOLOGY® 2025 in San Antonio.In 2010, I received a K08 award from the National Institutes of Health (NIH) to receive training in systems neuroscience with Emery Brown, MD, PhD, to explore a new approach to developing anesthetic reversal agents. Rather than trying to block anesthetics from binding to receptors, I began to test drugs known to promote wakefulness and found that methylphenidate restores conscious behaviors and awake EEG patterns in rats anesthetized with isoflurane and propofol. Methylphenidate is a reuptake inhibitor for dopamine and norepinephrine, both of which are known to promote arousal. Our subsequent work demonstrated that the anesthetic reversal effect of methylphenidate is mediated primarily by dopamine, rather than norepinephrine. We also found that dextroamphetamine, a dopamine releasing agent, is even more potent than methylphenidate in reversing anesthetic-induced unconsciousness. We then discovered that electrical deep brain stimulation of the ventral tegmental area (VTA), a critical dopamine nucleus in the midbrain, rapidly restores consciousness in rodents anesthetized with isoflurane, sevoflurane, propofol, dexmedetomidine, and fentanyl. Additional work using optogenetics revealed that selective activation of dopamine cells in the VTA is sufficient to reverse anesthetic-induced unconsciousness. These studies established a critical role for dopamine in arousal and demonstrated that anesthetic reversal is feasible by activating endogenous neural circuits that promote wakefulness. Activating dopaminergic neurotransmission is one of several approaches that may be used to reverse anesthetic-induced unconsciousness. With leading investigators in the field, we recently published a review article in Anesthesiology describing ongoing efforts to develop anesthetic reversal agents (Anesthesiology 2025;143:1049-89). I look forward to the time when anesthetic reversal agents become available for clinical use, which will improve patient safety and allow practitioners to better control the arousal states of their patients. Looking back at my journey as a physician-scientist, I cannot overstate the importance of the FAER MRTG in launching my career and the mentors who inspired and encouraged me along the way. With the headwinds facing anesthesiology research today, I believe it is our collective duty to support the next generation of investigators who will advance our specialty. Disclosure: Dr. Solt is Cofounder and Chair of the Scientific Advisory Board of Ekawa Therapeutics.Ken Solt, MD, 2006 FAER Mentored Research Training Grant Recipient, 2025 FAER-Helrich Research Lecturer, Vice Chair of Research, Department of Anesthesiology, Mass General Brigham, and Edward Mallinckrodt Jr. Professor of Anaesthesia, Harvard Medical School, Boston, Massachusetts.