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THE GENERAL ANESTHESIA RECEPTOR FRANKS. LABELLA* Classical Lipoid Theories of General Anesthesia 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 ofsimpler 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 Author's investigations were supported by the Saint Boniface Hospital Research Foundation , Richardson Foundation, Children's Hospital Research Foundation, Manitoba Heart Foundation, and the Medical Research Council of Canada. *University of Manitoba, Faculty of Medicine, Department of Pharmacology and Therapeutics, Winnipeg, Manitoba, Canada R3E OW3.© 1982 by The University of Chicago. All rights reserved 0031-5982/82/2502-0281$0l.00 322 Frank S. La Bella · General Anesthesia Receptor these effects on lipid molecules translated into modified cellular function ? Any number ofmechanisms can theoretically explain the second of these issues, although their experimental verification is problematic. For example, lipids clearly contribute to the maintenance of critical molecular conformations of membrane enzymes, ion channels, and receptors (recognition sites for endogenous ligands); disruption of lipid molecular orientation, thus, is transmitted to the protein component of the cell membrane mosaic. Hypotheses that specify lipid as membrane domains sensitive to anesthetic action suffer from serious limitations and inconsistencies. Important arguments against lipid as the sole or primary site of anesthetic action include, for example, the failure of all anesthetic agents to promote lipid changes in the same direction [3]. Furthermore, in many instances physical changes in membrane lipid structure are not detectable in the absence of irrelevantly high concentrations of the agents [4]. (For a detailed exposition of arguments against lipid as the site of action, see [5, 6].) However, Halsey, Green, and Wardley-Smith [7] feel that imposition of two alternatives, that is, lipid or protein, is a false dichotomy , and these investigators argue for "multi-site expansion" by anesthetics. Perhaps the most compelling argument against lipid theories are observations that some chemical congeners or isomers, differing from the anesthetic member only trivially in chemical and physical properties such as lipid solubility, show convulsant activity. Examples of molecular modifications that convert an anesthetic agent to a convulsant include (a) addition of a methyl group to the aliphatic side chain of barbiturates, (b) addition of a single double bond in the steroid nucleus, and (c) replacement of one fluorine atom in halothane by a hydrogen atom (see [8]). Evidence That Membrane Proteins, Not Lipids, Are Targetsfor Anesthetics General anesthetics have been shown to induce changes in conformation and properties of a large variety of purified proteins and protein complexes: actomyosin, microtubular protein, glutamic dehydrogenase, myoglobin, hemoglobin, luciferase, albumin, lactoglobulin, calciumdependent ATPase ofcardiac myofibrils, and receptors for acetylcholine (nicotinic), acetylcholine (muscarinic), dopamine, ouabain, opiates, aadrenergic ligands, and aequorin, a protein that emits light in the presence of ionized calcium (see [8]). Furthermore, a correlation between anesthetic potency and protein-perturbation potency has been demonstrated for membrane receptors, enzymes, and ion...


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