July 3, 1998 What is the precise physical and mental state produced by anesthetic drugs? Despite a century and a half of reliance on these drugs to advance life-saving surgical techniques, physicians and scientists still don't know the answer to that question. "All we know for sure when we give patients anesthetic drugs is that they don't respond to pain and they don't remember the experience," says Roderic G. Eckenhoff, MD, an associate professor of anesthesiology and physiology. "We don't know how the drugs work or even where in the central nervous system they act to produce their effects on consciousness." Eckenhoff is leading a multidisciplinary research effort to identify the molecular mechanism -- or mechanisms -- of action for the small, two- or three-carbon molecules that produce anesthesia.
For years, researchers in this area have searched in vain for a single molecular interaction, whether with a receptor protein or cell-membrane lipid, to explain the drugs' effects. Eckenhoff suggests that, while it would be simpler for investigators if this were the case, it is more likely that the drugs act at multiple sites in a complex, coordinated manner. "We're beginning to understand how these small molecules interact with and bind to proteins, and how that binding changes protein structure and dynamics. It would be premature for us to link these changes with anesthesia, but our early evidence is pointing toward a generalized mechanism of action for inhaled anesthetics."
While the ultimate goal of the experimental studies is to improve safety and extend the control physicians have over the anesthetic state, Eckenhoff also hopes the project will build a base of new knowledge that will lead indirectly to other advances. "There will be spinoffs from this work in other fields, some as yet unanticipated, others at least speculatively in view. For example, there's a small literature building now on the use of these kinds of drugs for tissue and organ preservation, and thus our research could contribute to transplantation medicine."Also, anesthesia is not like ordinary sleep or other types of unconsciousness, Eckenhoff notes, raising questions about the nature of consciousness itself that might be illuminated by the studies. "Once we better understand how unconsciousness works, chances are we'll have new insight into how consciousness works."
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