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 gamma-aminobutyric acidA 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 gamma-aminobutyric acidA receptor function. Studies on knock-in animals showed that etomidate and propofol act via gamma-aminobutyric acidA receptors containing beta3 subunits, whereas gamma-aminobutyric acidA receptors including alpha2 and gamma subunits mediate the myorelaxant properties of diazepam. These findings suggest that a large fraction of gamma-aminobutyric acidA receptors in the spinal cord assemble from alpha2, beta3 and most probably gamma2 subunits. The hypnotic actions of etomidate are mediated by beta3-containing gamma-aminobutyric acidA receptors expressed in the brain. In contrast, gamma-aminobutyric acidA receptors harbouring beta2 subunits produce sedation, but not hypnosis. Furthermore, there is growing evidence that extrasynaptic gamma-aminobutyric acidA receptors in the hippocampus containing alpha5 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.