Seeking a key

to anesthetic susceptibility

Published December 01 2017

With an estimated 234 million surgeries performed around the world each year, anesthesia is considered one of the most important medical discoveries in the past 200 years. Drugs in this broad group prevent a patient from being conscious and from feeling pain during surgery, yet we still don’t fully understand how many anesthetics work. A recent paper in the Journal of Lipid Research sheds new light on the molecular mechanism underlying anesthesia and proposes a noninvasive technique to monitor its activity.

M. Francesca Cordeiro’s research group at the University College London Institute of Ophthalmology began this research after a close relative of one of the authors experienced a complication from general anesthesia. For most people, general anesthetics work well and are exceptionally safe; however, up to 2 percent of the population is resistant to anesthesia. In extreme cases, patients that appear unconscious are awake and can sometimes feel pain, but they remain paralyzed. While awareness during general anesthesia is rare, it is distressing for the patient and can cause problems, including post-traumatic stress disorder, well after surgery.

Most drug molecules affect the body through binding specific protein receptors, “like a key fitting a lock,” Cordeiro and first author Benjamin Michael Davis wrote in response to questions about the study. However, researchers have been unable to identify the receptors that many anesthetic molecules bind to. Researchers “have a bunch of keys but don’t know what locks they fit into,” Cordeiro and Davis wrote. “This is a problem because the way we typically design better drug molecules is by studying the receptors they interact with, and without knowing the receptors, we don’t know which key fits which lock and how this interaction could be made better.” Researchers have debated over the past 100 years whether anesthetics “interact directly with a receptor, like a key in lock, or instead act at a distance, without directly interacting with a receptor, like a wireless car key fob,” they wrote.

Previous research indicates that anesthetics might interact with the cell membrane where protein receptors are housed and, by changing some unknown membrane property, indirectly alter receptor activity to induce unconsciousness and pain insensitivity. As cell membranes are composed of fat, some scientists have suggested that changes in membrane fluidity could be responsible for the indirect method of anesthesia activity. However, this seems unlikely, as normal changes in body temperature can cause bigger alterations in membrane fluidity than anesthetics can; we don’t usually lose consciousness after a day in the sun or after exercise (when our internal body temperature increases).In the recent study, Davis and colleagues proposed that anesthetics indirectly affect receptors by changing membrane dipole potential and not cell-membrane fluidity. The membrane dipole potential is an electrical potential that arises from the arrangement of fat (phospholipids and sterols) and water molecules in the cell membrane. Davis and colleagues discovered that some anesthetic molecules could change the membrane dipole potential. They suggest that this could act like a car fob signal, causing an indirect change in receptor function and thereby opening the lock.

The researchers believe their findings will help identify which receptor proteins are involved in anesthetic activity, thereby facilitating the design of more potent anesthetics with fewer side effects. Additionally, membrane dipole potential can be measured in real time using a small fluorescent dye molecule called di-8-ANEPPs. This has been done only in artificial membranes, building on Cordeiro’s extensive experience with developing retinal-based contrast agents for the early diagnosis of neurodegenerative disease in the clinic. However, Davis and colleagues believe this dye could be used in conjunction with an established retinal imaging technique called confocal scanning laser ophthalmoscopy to develop a simple and noninvasive test to evaluate a patient’s susceptibility to anesthesia. This noninvasive test has the potential to minimize the risk of anesthetic awareness in patients and provide a much-needed tool to quickly and reliably assess anesthetic activity.

Much of this work was done using artificial membrane systems, so the next step is to use rodent models to investigate whether changes in the dipole potential can be detected in the retina of rodents upon anesthesia induction. After testing in a preclinical setting, the researchers hope to conduct a clinical trial, Cordeiro and Davis wrote, adding that the potential to monitor anesthetic activity with noninvasive retinal imaging is exciting, “as it has the potential to identify patients at risk of anesthetic awareness before undergoing surgery.”

Rachel Goldberg Rachel Goldberg is a molecular biologist and postdoctoral research fellow at the Johns Hopkins University School of Medicine.