Knockin' on the door of general anesthetic mechanisms: but will U.S. researchers be shut out?

I n the last 3 years, we have witnessed exciting new developments in our understanding of anesthetic mechanisms. This editorial comments on the review by Sonner et al. (1) and describes recent key advances in the field. In a recent commentary I drew attention to the growing perception of the importance of ion channels, especially -aminobutyric acid (GABA)-A and N-methyl-daspartic acid (NMDA) receptors, to general anesthetic mechanisms (2). Here I will first discuss the exhaustive review by Sonner et al. that appears within these pages (1), and will then describe the current state of excitement within the field. Finally, I note that many of the most critical recent observations were made in Europe, and that the U.S. research community may need to work hard to stay in the race. Research on anesthetic mechanisms was stagnant for much of the 20th century, primarily because of the almost universal acceptance of the dogma of nonspecific anesthetic action—the so-called “Lipid Theory.” In the 1960s and 70s, descriptions of general anesthetic action in the major textbooks recalled the story of the Emperor’s New Clothes—long on imagination, but transparently lacking in substance. The overthrow of this dogma occurred slowly over the last two decades, with Nick Franks and his coworkers playing a central role, steadily chipping away at the foundations of the Lipid Theory (3–5). In many ways, this process resembled the Cold War—years of attrition, before the edifice collapsed and the Berlin Wall was dismantled over a few short days (this was perhaps most evident at a conference held in Calgary in 1997). A sign that the changes are being consolidated and “receptor-based” theories are now ascendant was the recent publication of perhaps the first modern and truly scientific description of anesthetic mechanisms within a major textbook (6). Despite this, education remains an important priority within the field. I recently spoke at a department in which the senior faculty were unaware that glutamate was the fast excitatory neurotransmitter in the brain, but were apparently convinced that acetylcholine and norepinephrine performed the same roles in the central nervous system that they do in the autonomic nervous system. Sonner et al. provide an extensive review of recent developments (1). This group, a multicenter research program based at the University of California, San Francisco (UCSF), has long pursued a highly collaborative and interactive strategy that centered around twice-yearly meetings at which a diverse group of investigators focuses intensely on novel issues and experiments. These gatherings have occurred outside of the framework of the traditional conferences, but bring together talented minds from around the world who share an interest in problems of general anesthetic action. Another successful anesthesia research group in St. Louis has adopted an equally successful, but more local approach, by interacting extensively with the strong basic science community at Washington University. Sonner et al. present persuasive, but perhaps not completely definitive, arguments in favor of certain neurotransmitter receptors and ion channels as anesthetic targets, while eliminating others from consideration. The review focuses on the ability of general anesthetics to abolish purposeful movement in response to a noxious stimulus, an endpoint introduced by Eger and enshrined in the “MAC” concept (7,8). As they carefully point out, Sonner et al. ’s conclusions need not apply to other anesthetic end-points, such as hypnosis, amnesia and analgesia. Since I agree with much of what the authors have written, I do not intend to reprise their scholarly efforts here. I will instead highlight a few of those very recent experiments that I consider most likely to be influential in the near future. Accepted for publication June 16, 2003. Address correspondence and reprint requests to Neil L. Harrison, PhD, Professor and Director, C.V. Starr Laboratory of Molecular Neuropharmacology, Department of Anesthesiology, Weill Medical College of Cornell University, New York, NY 10021. Address e-mail to [email protected].