Molecular interactions of anaesthetics with biological membranes

1. There is not yet a consensus as to which of the neuronal membranes, which molecular component of any particular membrane or what specific function of the membrane is critical for general anaesthesia. 2. However, when considering anaesthetic effects on different synapses, with neurotransmitter receptors, ion channels etc., the unifying central concept is action at a membrane level. 3. This paper will review the general evidence for this unifying hypothesis, and consider the apparent exceptions and limitations. 4. The membrane hypothesis is usually stated in the form of the Meyer and Overton "rule" relating anaesthetic potency to hydrophobic solubility. 5. The relationship applies to inhaled anaesthetics with potencies over a 100,000-fold range and has been described as one of the most powerful correlations in biology. 6. Finding additional compounds that confirm this correlation is not likely to elucidate further the anaesthetic mode of action, and concentrating on the apparent exceptions to the hypothesis may prove to be a better approach. 7. The apparent exceptions to the membrane hypothesis include some of the physiological and convulsant gases as well as higher members of a homologous series of hydrophobic compounds above the so-called "cut-off" effect. 8. The apparent limitations include two of the most widely used clinical agents--enflurane and isoflurane. 9. This paper will include some new data characterizing the anaesthetic site of action using a diverse group of anaesthetics (including some of the exceptions already mentioned). 10. The evidence is against an earlier hypothesis that there is a bimodal distribution of the molecular sites.