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 gamma-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 gamma-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.
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 gamma-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 gamma-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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Authors: Robert C Dutton; Yi Zhang; Caroline R Stabernack; Michael J Laster; James M Sonner; Edmond I Eger Journal: Anesthesiology Date: 2003-06 Impact factor: 7.892
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Authors: U Rudolph; F Crestani; D Benke; I Brünig; J A Benson; J M Fritschy; J R Martin; H Bluethmann; H Möhler Journal: Nature Date: 1999-10-21 Impact factor: 49.962
Authors: Lindsay M McCracken; James R Trudell; Beth E Goldstein; R Adron Harris; S John Mihic Journal: Neuropharmacology Date: 2009-11-11 Impact factor: 5.250
Authors: Radovan Spurny; Bert Billen; Rebecca J Howard; Marijke Brams; Sarah Debaveye; Kerry L Price; David A Weston; Sergei V Strelkov; Jan Tytgat; Sonia Bertrand; Daniel Bertrand; Sarah C R Lummis; Chris Ulens Journal: J Biol Chem Date: 2013-01-30 Impact factor: 5.157
Authors: Radovan Spurny; Sarah Debaveye; Ana Farinha; Ken Veys; Ann M Vos; Thomas Gossas; John Atack; Sonia Bertrand; Daniel Bertrand; U Helena Danielson; Gary Tresadern; Chris Ulens Journal: Proc Natl Acad Sci U S A Date: 2015-04-27 Impact factor: 11.205