General anesthetics have additive actions on three ligand gated ion channels.
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.


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.
Jenkins
Andrew
A
Department of Anesthesiology, Emory University School of Medicine, 1462 Clifton Rd NE Suite 420, Atlanta, GA 30322, USA. ajenki2@emory.edu
Lobo
Ingrid A
IA
Gong
Diane
D
Trudell
James R
JR
Solt
Ken
K
Harris
R Adron
RA
Eger
Edmond I
EI
D018681:Anesthetics, General / Q000494:pharmacology*; D000818:Animals; D002725:Chloroform / Q000008:administration & dosage / Q000494:pharmacology; D004594:Electrophysiology; D006221:Halothane / Q000008:administration & dosage / Q000494:pharmacology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D007530:Isoflurane / Q000008:administration & dosage / Q000494:pharmacology; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010424:Pentobarbital / Q000008:administration & dosage / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D018009:Receptors, Glycine / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D014982:Xenopus laevis
D018681:Anesthetics, General; D007473:Ion Channels; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D002725:Chloroform; D007530:Isoflurane; D010424:Pentobarbital; D006221:Halothane