RESUMO
BACKGROUND: The authors have previously described that the gamma-aminobutyric acid type A (GABAA) receptor beta 2N265S mutation results in a knock-in mouse with reduced sensitivity to etomidate. After recovery from etomidate anesthesia, these mice have improved motor performance and less slow wave sleep. Because most clinically used anesthetics produce hypothermia, the effect of this mutation on core body temperature was investigated. METHODS: The effect of etomidate and propofol on core body temperature were measured using radiotelemetry in freely moving GABAA receptor beta 2N265S mutant mice and wild-type controls. RESULTS: beta 2N265S mutant mice have a reduced hypothermic response to anesthetic doses of etomidate compared with wild-type controls and after a transient loss of righting reflex regain normothermia more rapidly compared with wild-type controls. Subanesthetic doses of etomidate produce hypothermia, which was not observed in the mutant mice. Vehicle administration resulted in a stress-induced hyperthermic response in both genotypes. Propofol produced a hypothermic response that was similar in both genotypes. CONCLUSIONS: The GABAA receptor beta 2 subunit mediates a significant proportion of the hypothermic effects of etomidate. As the beta 2 subunit mediates postrecovery ataxia and sedation, anesthetic agents that do not have in vivo potency at beta 2 subunit-containing receptors offer the potential for surgical anesthesia with improved recovery characteristics.
Assuntos
Temperatura Corporal/efeitos dos fármacos , Etomidato/toxicidade , Hipotermia/induzido quimicamente , Hipotermia/fisiopatologia , Subunidades Proteicas/fisiologia , Receptores de GABA/fisiologia , Animais , Temperatura Corporal/genética , Etomidato/antagonistas & inibidores , Hipotermia/genética , Camundongos , Camundongos Mutantes , Subunidades Proteicas/genética , Receptores de GABA/genética , Receptores de GABA-A , Fatores de TempoRESUMO
The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABA(A) receptors, with selectivity for beta2 and beta3 subunit-containing receptors determined by a single asparagine residue. We generated a genetically modified mouse containing an etomidate-insensitive beta2 subunit (beta2 N265S) to determine the role of beta2 and beta3 subunits in etomidate-induced anesthesia. Loss of pedal withdrawal reflex and burst suppression in the electroencephalogram were still observed in the mutant mouse, indicating that loss of consciousness can be mediated purely through beta3-containing receptors. The sedation produced by subanesthetic doses of etomidate and during recovery from anesthesia was present only in wild-type mice, indicating that the beta2 subunit mediates the sedative properties of anesthetics. These findings show that anesthesia and sedation are mediated by distinct GABA(A) receptor subtypes.
