How anaesthetic drugs interact with the brain to block pain and induce a coma-like, memory-free state has been a mystery since anaesthesia was first used in operating theatres more than 160 years ago.
The debate has divided the anaesthesia research community into two camps: those that believe that anaesthetia interacts primarily on the cell membrane (the lipid bilayer) of nerve cells, perhaps altering it to the point that embedded proteins cannot function normally, and those who think that the membrane proteins themselves are altered directly.
New evidence to support the latter position, that anaesthesia interacts and alters membrane proteins directly, comes from a team at Weill Cornell Medical College who have found that the activity of ion channel proteins that are important for cell-to-cell communication is markedly reduced when anaesthetics are applied.
“This is, to our knowledge, the first demonstration that anaesthetics alter the function of relevant ion channels without altering properties of the cell membranes,” said lead investigator Hugh Hemmings, professor and chair of anaesthesiology at Weill Cornell, who worked in close collaboration with Olaf Andersen, a lipid bilayer expert and professor of physiology and biophysics at Weill Cornell, who has developed methods to quantify the membrane-perturbing effects of drugs and other molecules.
Their studies tested clinically relevant concentrations of isoflurane; an important distinction, said first author Karl Herold, as previous research that found the membrane was altered used much higher doses of isoflurane than would ever be used in patients.
“Drugs are not perfect, they always have side effects,” said Herold. “You can only improve drugs if you know how they work, which means that you need to know when drugs have non-specific or undesired membrane effects.
“Now that we have a basic understanding of how anaesthetics affect cells in the central nervous system, we have knowledge to improve them,” he added. “In the future, we may be able to design anaesthetics that do just what we want them to do, and not what we don’t.”
Herold, K.F., et al. (2014) J. Gen. Physiol. doi:10.1085/jgp.201411172