Mechanisms of Intravenous Anesthetic Action

General anesthesia consists of key separable and independent neurobiological end points. Each of these involves distinct but possibly overlapping neuroanatomical and molecular mechanisms that converge to produce the characteristic behavioral end points of anesthesia: amnesia, unconsciousness, and immobility. The potency of various structurally dissimilar general anesthetics correlates with their solubilities in oil (lipophilicity), consistent with critical interactions with hydrophobic molecular targets. The pharmacologically relevant binding sites of general anesthetics are lipophilic cavities in proteins identified by a combination of site-directed mutagenesis and high-resolution structural analysis of anesthetic binding. Specific point mutations render putative target proteins insensitive to certain general anesthetics. Expression of these mutations in mice reduces anesthetic potency for specific end points.