The General Anesthesia Receptor

It has long been recognized that, for a given compound, drug potency for depressing cellular function is closely correlated with lipid solubility. This correlation is one of the most striking in pharmacology, and compounds may differ in potency by more than four orders of magnitude. The correlation between hydrophobicity and neurodepressant potency was first explicitly put forth as the Meyer-Overton theory of narcosis. It applies to the general anesthetic state seen in animals and humans as well as to depression of simpler organisms, nonneural tissues, and even single cells. It seems reasonable to assume that an indifferent lipid substance may dissolve preferentially in the lipoidal substance of the cell membrane and, in some way, interfere with normal neuronal function to produce the anesthetic, or narcotic, state. One can envision a number of ways in which a lipophilic compound might perturb cellular membranes; as knowledge of membrane structure has developed, so have lipid theories of anesthetic action become more sophisticated. The criticalvolume hypothesis views occupation and expansion of the cell membrane as the underlying basis for cellular perturbation. Increased fluidity and alterations in the phase-transition specify alternative mechanisms for perturbation by drugs of the lipid orientation in the cell membrane. (For recent reviews of lipid theories of anesthesia, see [1, 2].) Two obvious questions are raised by any hypothesis which invokes membrane lipids as a target of anesthetic action: first, do measurable alterations in the physical chemistry of membrane lipids result from exposure to clinical concentrations of the agents; and, second, how are