A hypothesis about the endogenous analogue of general anesthesia.

Abstract

The advent of general anesthesia remains one of the most important advances in the history of medicine. Although the first popular demonstration of general anesthesia occurred more than 150 years ago at the now-famous ether dome of the Massachusetts General Hospital, the mechanism by which it occurs is still debated (1). Surprisingly, among all of the questions asked about general anesthesia, the important issue of if there is an endogenous analogue of the process is rarely discussed. This situation is in distinction to the usual course of events when an exogenous natural product is found to have biological activity in that much activity is devoted to a search for the endogenous counterpart. Think, for example, about the opiates and the endorphins. As a formal proposition the question is if the brain or body makes compounds that have the properties and mode of action of general anesthetics. The issue reduces to what, if any, natural process are the general anesthetics mimicking. This question surfaces now because of the recent discovery of a sleep-inducing lipid, oleamide, in the cerebrospinal fluid (CSF) of sleep-deprived cats (2, 3). Oleamide since has been shown to affect diverse membrane proteins (4), has a structure expected to perturb the fluidity of membrane lipids, and is accompanied by a membrane-bound brain enzyme that rapidly inactivates the compound (3, 5). It is therefore possible that the way oleamide operates is unusual in that it perturbs lipid matrices either free or complexed to proteins and protein assemblies. This concept is worth considering because it would represent a new form of regulation distinct from the usual receptor-ligand interaction. The main chemical facts about general anesthetics concern their diverse nature, hydrophobicity, and general lack of stereospecificity. The oldest correlate is called the Meyer–Overton rule, which …