Molecular and systemic mechanisms of general anaesthesia: The 'multi-site and multiple mechanisms' concept

Purpose of review: Amnesia, hypnosis and immobility are essential components of general anaesthesia. This review highlights recent advances in our understanding of how these components are achieved at a molecular level. Recent findings: Commonly used volatile anaesthetic agents such as isoflurane or sevoflurane cause immobility by modulating multiple molecular targets predominantly in the spinal cord, including γ-aminobutyric acid _A receptors, glycine receptors, glutamate receptors and TREK-1 potassium channels. In contrast, intravenously applied drugs such as propofol or etomidate depress spinal motor reflexes almost exclusively via enhancing γ-aminobutyric acid_A receptor function. Studies on knock-in animals showed that etomidate and propofol act via γ-aminobutyric acid_A receptors containing β₃ subunits, whereas γ-aminobutyric acid_A receptors including α₂ and γ subunits mediate the myorelaxant properties of diazepam. These findings suggest that a large fraction of γ-aminobutyric acid_A receptors in the spinal cord assemble from α₂, β₃ and most probably γ₂ subunits. The hypnotic actions of etomidate are mediated by β₃-containing γ-aminobutyric acid_A receptors expressed in the brain. In contrast, γ-aminobutyric acid_A receptors harbouring β₂ subunits produce sedation, but not hypnosis. Furthermore, there is growing evidence that extrasynaptic γ-aminobutyric acid _A receptors in the hippocampus containing α₅ subunits contribute to amnesia. Summary: Clinical anaesthesia is based on drug actions at multiple anatomical sites in the brain. The finding that amnesia, hypnosis and immobility involve distinct molecular targets opens new avenues for developing improved therapeutic strategies in anaesthesia.