Some scientific reflections on possible mechanisms of general anaesthesia

The challenge to achieve a gestalt understanding of general anaesthesia is really dependent upon an understanding of the elusive concept of consciousness. Until very recently, anaesthesia has been understood to depend fundamentally on the lipid solubility of anaesthetic agents, unsurprisingly a misleading view which has followed from the greater simplicity of lipid chemistry compared with protein chemistry and, it is contended here, from a serious misunderstanding of the older experimental data. Nonetheless, because an over-simplistic view of lipids pertains in much pharmacological thinking about anaesthesia, this paper devotes some attention to potentially relevant aspects of lipid function and also to concepts of anaesthesia which are based on the properties of intracellular and extracellular water. It is argued that the more correct pharmacological explanation is likely to be action at hydrophobic sites of crucial functional molecules, most plausibly protein molecules: empirical data which support such actions are presented and considered. Anaesthetic actions on a range of such proteins are discussed, with the emphasis on general neurophysiological principles, with the intent of avoiding the mire into which detailed consideration of actions at specific sites of putative function in the central nervous system can lead. Those experimentally-documented actions include influences on the proteins which constitute the Na(+)-ion conductance channels in axonal membranes (which are the basis for action potentials); on the Ca(2+)-ion channels which are crucial for neurotransmitter secretion from nerve terminals; on the properties of the ion channels in the post-synaptic membranes of the neurons which are the targets for transmitter action; on components of the "second messenger" systems of target neurons; as well as actions on metabolically significant enzymes (notably cytochrome P450). The overall argument is that the concept of anaesthetic actions on lipids should be abandoned in favour of one which is consistent with the general pharmacological principle of drug action at specific receptor sites, i.e. a targeted action at unique loci on relevant proteins.