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ANESTHETIC PHARMACOLOGY

General Anesthetics Have Additive Actions on Three Ligand Gated Ion Channels

Andrew Jenkins, PhD^*, Ingrid A. Lobo, PhD, Diane Gong, PharmD, James R. Trudell, PhD, Ken Solt, MD, R. Adron Harris, PhD, and Edmond I. Eger, II, MD^||

From the *Department of Anesthesiology, Emory University, Atlanta, Georgia; Waggoner Center for Alcohol and Addiction Research, Section of Neurobiology and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas; Department of Anesthesiology, Stanford University, Stanford, California; Department of Anesthesia and Critical Care, Massachusetts General Hospital and Department of Anesthesia, Harvard Medical School, Boston Massachusetts; and ||Department of Anesthesia and Perioperative Care, University of CA, San Francisco, California.

Address correspondence and reprint requests to Dr. Andrew Jenkins, Department of Anesthesiology, Emory University School of Medicine, 1462 Clifton Rd NE Suite 420, Atlanta, GA 30322. Address e-mail to ajenki2{at}emory.edu.

BACKGROUND: The purpose of this study was to determine whether pairs of compounds, including general anesthetics, could simultaneously modulate receptor function in a synergistic manner, thus demonstrating the existence of multiple intraprotein anesthetic binding sites.

METHODS: Using standard electrophysiologic methods, we measured the effects of at least one combination of benzene, isoflurane (ISO), halothane (HAL), chloroform, flunitrazepam, zinc, and pentobarbital on at least one of the following ligand gated ion channels: N-methyl-d-aspartate receptors, glycine receptors and -aminobutyric acid type A receptors.

RESULTS: All drug-drug-receptor combinations were found to exhibit additive, not synergistic modulation. ISO with benzene additively depressed N-methyl-d-aspartate receptors function. ISO with HAL additively enhanced glycine receptors function, as did ISO with zinc. ISO with HAL additively enhanced -aminobutyric acid type A receptors function as did all of the following: HAL with chloroform, pentobarbital with ISO, and flunitrazepam with ISO.

CONCLUSION: The simultaneous allosteric modulation of ligand gated ion channels by general anesthetics is entirely additive. Where pairs of general anesthetic drugs interact synergistically to produce general anesthesia, they must do so on systems more complex than a single receptor.

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