Tag Archives: General anesthesia

How general anesthesia works

People have been theorizing how general anesthesia works since there has been general anesthesia.  The first useful one was diethyl ether (by definition what lipids dissolve in).  Since the brain has the one of the highest fat contents of any organ, the mechanism was obvious to all.  Anesthetics dissolve membranes.  Even the newer anesthetics look quite lipophilic — isoflurane CF3CHCL O CF2H screams (to the chemist) find me a lipid to swim in.  One can show effects of lipids on artificial membranes but the concentrations to do so are so high they would be lethal.

Attention shifted to the GABA[A] receptor, because anesthetics are effective in potentiating responses to GABA  — all the benzodiazepines (valium, librium) which bind to it are sedating.  Further evidence that a protein is involved, is that the optical isomers of enflurane vary in anesthetic potency (but not by very much — only 60%).  Lipids (except cholesterol) just aren’t optically active.  Interestingly, alfaxolone is a steroid and a general anesthetic as well.

Well GABA[A] is an ion channel, meaning that its amino acids form alpha helices which span the membrane (and create a channel for ion flow).  It would be devilishly hard to distinguish binding to the transmembrane part from binding to the membrane near it. [ Science vol. 322 pp. 876 – 880 2008 ] Studied 4 IV anesthetics (propofol, ketamine, etomidate, barbiturate) and 4 gasses (nitrous  oxide, isoflurance, devoflurane, desflurane) and their effects on 11 ion channels — unsurprisingly all sorts of effects were found — but which ones are the relevant.

All this sort of stuff could be irrelevant, if a new paper is actually correct [ Neuron vol. 102 pp. 1053 – 1065 ’19 ].  The following general anesthetics (isoflurane, propofol, ketamine and desmedtomidine) all activate cells in the hypothalamus (before this anesthetics were thought to work by ultimately inhibiting neurons).  They authors call these cells AANs (Anesthesia Activated Neurons).

They are found in the hypothalamus and contain ADH.  Time for some anatomy.  The pituitary gland is really two glands — the adenohypophysis which secretes things like ACTH, TSH, FSH, LH etc. etc, and the neurohypophysis which secretes oxytocin and vasopressin (ADH) directly into the blood (and also into the spinal fluid where it can reach other parts of the brain.  ADH release is actually from the axons of the hypothalamic neurons.  The AANs activated by the anesthetics release ADH.

Of course the workers didn’t stop there — they stimulated the neurons optogenetically and put the animals to sleep. Inhibition of these neurons shortened the duration of general anesthesia.

Fascinating (if true).  The next question is how such chemically disparate molecules can activate the AANs.  Is there a common receptor for them, and if so what is it?

Happy fiscal new year !