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.

Effects of acamprosate on neuronal receptors and ion channels expressed in Xenopus oocytes.

Background: Acamprosate (calcium acetylhomotaurinate) has proven to be a moderately effective pharmacological adjunct for the treatment of alcoholism. However, the central nervous system mechanism by which acamprosate reduces alcohol relapse remains unclear. Here we survey a number of metabotropic receptors, ligand-gated ion channels, and voltage-gated ion channels, to determine if acamprosate has actions at these sites in the central nervous system.

Mouse chromosome 7 harbors a quantitative trait locus for isoflurane minimum alveolar concentration.

Background: The minimum alveolar concentration (MAC) of isoflurane is a quantitative trait because it varies continuously in a population. The location on the genome of genes or other genetic elements controlling quantiative traits is called quantitative trait loci (QTLs). In this study we sought to detect a quantitative trait locus underlying isoflurane MAC in mice.

Chirality in anesthesia II: stereoselective modulation of ion channel function by secondary alcohol enantiomers.

Chirality has been proposed as a means for distinguishing relevant from irrelevant molecular targets of action, but the sensitivity and specificity of this test is unknown for volatile anesthetics. We applied enantiomers of two chiral anesthetic alcohols (2-butanol and 2-pentanol) that are enantioselective for the minimum alveolar concentration (MAC) preventing movement in 50% of animals and one (2-hexanol) that was not to frog oocytes. Each oocyte expressed one of three anesthetic-sensitive ion channels: a Twik-related-spinal cord K+ (TRESK) channel, a gamma-amino butyric acid type A (GABA(A)) receptor and an N-methyl-d-aspartate (NMDA) receptor.

The effect of three inhaled anesthetics in mice harboring mutations in the GluR6 (kainate) receptor gene.

Combinations of GluR5-GluR7, KA1, and KA2 subunits form kainate receptors, a subtype of excitatory ionotropic glutamate receptors. Isoflurane enhances the action of kainate receptors comprising GluR6 subunits expressed in oocytes. To test whether alterations of the GluR6 subunit gene affect the actions of inhaled anesthetics in vivo, we measured the minimum alveolar concentration of desflurane, isoflurane, and halothane in mice lacking the kainate receptor subunit GluR6 (GluR6 knockout mice) and mice with a dominant negative glutamine/arginine (Q/R) editing mutation in membrane domain 2 of the GluR6 receptor (GluR6 editing mutants), which increases the calcium permeability of kainate receptors containing GluR6Q.

Mutation of KCNK5 or Kir3.2 potassium channels in mice does not change minimum alveolar anesthetic concentration.

Unlabelled: Several reports suggest that clinically used concentrations of inhaled anesthetics can increase conductance through noninactivating potassium channels and that the resulting hyperpolarization might decrease excitability, thereby leading to the anesthetic state. We speculated that animals deficient in such potassium channels might be resistant to the effects of anesthetics. Thus, in the present study, we measured the minimum alveolar anesthetic concentration (MAC) needed to prevent movement in response to a noxious stimulus in 50% of adult mice lacking functional KCNK5 potassium channel subunits and compared these results with those for heterozygous and wild-type mice.

Acetylcholine receptors and thresholds for convulsions from flurothyl and 1,2-dichlorohexafluorocyclobutane.

Unlabelled: There are acetylcholine receptors throughout the central nervous system, and they may mediate some forms and aspects of convulsive activity. Most high-affinity binding sites on nicotinic acetylcholine receptors for nicotine, cytisine, and epibatidine in the brain contain the beta2 subunit of the receptor. Transitional inhaled compounds (compounds less potent than predicted from their lipophilicity and the Meyer-Overton hypothesis) and nonimmobilizers (compounds that do not produce immobility despite a lipophilicity that suggests anesthetic qualities as predicted from the Meyer-Overton hypothesis) can produce convulsions.

Heteromeric nicotinic inhibition by isoflurane does not mediate MAC or loss of righting reflex.

Background: Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in the mechanism of action of isoflurane as they are inhibited at subanesthetic concentrations. Despite clear evidence for nicotinic inhibition at relevant isoflurane concentrations, it is unclear what behavioral result ensues, if any.

Methods: The authors have modeled two behaviors common to all general anesthetics, immobility and hypnosis, as minimum alveolar concentration that prevents movement in response to a supramaximal stimulus (MAC) and loss of righting reflex (LORR).

Isoflurane hyperalgesia is modulated by nicotinic inhibition.

Background: The inhaled anesthetic isoflurane inhibits neuronal nicotinic acetylcholine receptors (nAChRs) at concentrations lower than those used for anesthesia. Isoflurane produces biphasic nociceptive responses, with both hyperalgesia and analgesia within this concentration range. Because nicotinic agonists act as analgesics, the authors hypothesized that inhibition of nicotinic transmission by isoflurane causes hyperalgesia.

The differential effect of halothane and 1,2-dichlorohexafluorocyclobutane on in vitro muscle contractures of patients susceptible to malignant hyperthermia.

Unlabelled: Malignant hyperthermia (MH) is an autosomal dominant, potentially fatal pharmacogenetic disorder of skeletal muscle. Approximately half of all known MH families show a linkage to the ryanodine receptor type 1 (RY1) gene. Although our knowledge of the diagnosis, genetics, and therapy of MH has improved, the exact pathogenesis and the role of volatile anesthetics as trigger substances for an MH crisis remain unknown.