General Anesthetics Have Additive Actions on Three Ligand-Gated Ion Channels

• Authors: Andrew Jenkins, Emory University; Ingrid A. Lobo, University of Texas at Austin; Diane Gong, University of Texas at Austin; James R. Trudell, Stanford University; Ken Solt, Harvard Medical School; R. Adron Harris, University of Texas at Austin; Edmond I Eger, University of California
• Journal Title: Anesthesia and Analgesia
• Volume: Volume 107, Number 2
• Publisher: Lippincott, Williams & Wilkins | 2008-08, Pages 486-493
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1213/ane.0b013e31817b70c1
• Subjects: Health Sciences, General; Health Sciences, Pharmacology; Biology, Molecular
• Keywords: GABA; glycine; NMDA; receptor; isoflurane; halothane; chloroform; pentobarbital; zinc; additivity; anesthetic mechanism

Abstract

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 intra-protein anesthetic binding sites. Methods Using standard electrophysiologic methods, we measured the effects of at least one combination of benzene, isoflurane, halothane, chloroform, flunitrazepam, zinc and pentobarbital on at least one of the following ligand gated ion channels: N-methyl-D-aspartate receptors (NMDARs), glycine receptors (GlyRs) and γ-aminobutyric acid type A receptors (GABAARs). Results All drug-drug-receptor combinations were found to exhibit additive, not synergistic modulation. Isoflurane with benzene additively depressed NMDAR function. Isoflurane with halothane additively enhanced GlyR function, as did isoflurane with zinc. Isoflurane with halothane additively enhanced GABAAR function as did all of the following: halothane with chloroform, pentobarbital with isoflurane, and flunitrazepam with isoflurane. Conclusions 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.