Anaesthetic mechanism--from molecular to biological aspects

The mechanism of anaesthesia is still a black box, although many investigators have been concerned about this theme since the 19th century. It is too complex to clarify the mode of anaesthetic action, as a variety of compounds have been adopted as anaesthetics. Hill coefficients calculated from the righting reflex dose-response curve in enflurane, isoflurane sevoflurane and halothane anaesthesia in a certain strain of mice were from 14 to 56. It shows that many factors are related to the mechanisms of anaesthetic actions. In this review, we adduce from our previous studies 2 approaches to study the anaesthetic mechanism. The pharmacogenetical approach is concerned with the mode of genetics in anaesthetic sensitivities in ddN and C57BL, 2 strains of mice and their hybrids, and distributions of neurotransmitters in each mouse brain. The sensitivity rates in enflurane and isoflurane anaesthesia are both 1.4 between ddN and C57BL. The rate is highest compared with precedent data. The F1 males from ddN females x C57BL males had a significantly higher ED50 than F1 males from the reciprocal crosses for both enflurane and isoflurane, indicating that enflurane resistance and isoflurane resistance are controlled by genes on the sex (X) chromosome. In the F2 progeny, we hypothesized that 1 gene was on the X chromosome and another gene was on the autosome. Although there were several differences among ddN, C57BL and their hybrids and several anaesthetics concerning distributions of neurotransmitters, neuropeptide Y, serotonine and methionine-enkephalin in the mouse brain, the relationship to the genetical analysis has been chaotic. The physicochemical approach is concerned with the confirmation of the action site of volatile anaesthetics in phospholipid bilayer membranes. It is suspected from Overton's experiment that the action site is not in the core of lipid bilayer but on the surface of membrane. It was demonstrated by 2 methodologies. Two-dimensional nuclear Overhauser effect spectrum in H1-NMR spectra of dipalmitoyl phosphatidylcholine (DPPC) vesicle membrane in the presence of methoxyflurane revealed from the existence of the cross-peak between the methoxy-proton and the choline methyl-proton that methoxyflurane molecule interacted only to the polar head of lipid membrane at lower temperatures.(ABSTRACT TRUNCATED AT 400 WORDS)