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Background

It has been over 160 years since the use of diethyl ether as a general anesthetic was publicly demonstrated, yet our mechanistic understanding of these vitally important drugs lags far behind that of most other major drug classes. Most modern inhaled anesthetics are derivatives of ether, and over the years have been developed to have improved pharmacokinetics, but they are still plagued by a lack of specificity with significant cardiovascular and respiratory side effects. It remains unclear how these drugs produce general anesthesia, a pharmacologically induced coma characterized by amnesia, unconsciousness, and immobility in response to painful stimuli (Hemmings et al., 2005b). Studies into their molecular mechanisms in the 1960s, which have their origins in the Meyer–Overton correlation of anesthetic potency with lipophilicity from 1900, led to a lipid-based theory involving a unitary mechanism of non-specific actions on the lipid bilayer (Meyer, 1899; Overton, 1901).

With technical advances in biochemistry and biophysics, specific targets were studied and identified. Pioneering studies showed that anesthetic interactions with proteins themselves, not necessarily involving lipid interactions, could explain anesthetic effects at a biochemical level (Franks and Lieb,1994). Animal studies showed that volatile anesthetics produce their immobilizing effects primarily by actions on the spinal cord (Antognini and Schwartz, 1993; Rampil et al., 1993), whereas unconsciousness and amnesia involve actions at supra-spinal centers (Eger et al., 2008). Membrane proteins including ion channels have been implicated as key mediators of the depressive effects of anesthetics on neuronal function. Many potential targets have been identified, and it has become clear that anesthetics act at multiple distinct targets in the central nervous system to produce the various component effects of the anesthetic state (multi-site hypothesis).