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05How Anaesthetics Are Thought to Work

How general anaesthetics produce unconsciousness is the oldest unsettled question in the subject. A single elegant correlation dominated it for eighty years, and the history of the field since is the history of that correlation's exceptions.

The correlation

Around the turn of the twentieth century two workers independently noticed something remarkable. Take a list of chemically unrelated substances that produce anaesthesia, and measure for each one both its potency and its solubility in olive oil relative to water. Plot one against the other and the points fall close to a straight line across several orders of magnitude. The more readily a substance dissolves in oil, the less of it is needed.

The natural interpretation, given what was known at the time, was that anaesthetics dissolve in the fatty membrane of the nerve cell and disturb it physically, and that the identity of the molecule is irrelevant beyond its solubility. This was an unusually satisfying result. It explained why substances with nothing chemically in common all produce the same state, it required no receptor and no specific target, and it made a quantitative prediction that held up well. It also had the property, dangerous in a theory, of being too tidy to question.

The exceptions

Three classes of exception accumulated, and each one is fatal to the simple reading.

The first is the cutoff effect. Within a chemical series, potency rises with oil solubility exactly as predicted until the molecules reach a certain size, and then abruptly stops rising, even though the solubility continues to increase. A membrane that simply dissolves whatever it is offered has no reason to behave that way. A binding site of fixed dimensions does.

The second is stereoselectivity. Two mirror-image forms of the same molecule have identical solubility in oil by definition, so they must be equally potent if solubility is what matters. They are not. For several agents one isomer is substantially more potent than the other. Only a target that is itself asymmetric, which means a protein, can tell them apart.

The third is the existence of compounds that fit the correlation perfectly and produce no anaesthesia at all. If oil solubility were sufficient, these could not exist.

The turn to proteins

The decisive experiment came in 1984 and was elegantly simple. A soluble protein, taken from an organism with no relevance to the nervous system, was shown to be inhibited by anaesthetics at the same concentrations that produce anaesthesia, in a preparation containing no lipid membrane whatever. Whatever anaesthetics are doing, they can do it to a protein directly. The correlation survives, but its explanation reverses: potency tracks oil solubility because the binding pockets on proteins are themselves greasy, not because the membrane is the target.

Work since has identified plausible molecular targets, principally certain ion channels that respond to the major inhibitory transmitter, certain excitatory receptors, and a family of background potassium channels. Different agents act on different combinations of these, which fits the twentieth-century clinical observation that the components of the state are separable.

What remains open

Identifying a molecular target is not the same as explaining unconsciousness. The gap between a channel whose behaviour is altered and a brain that has stopped supporting experience is enormous, and it is a gap of many levels: molecule, synapse, local circuit, network, whole cortex. Current work approaches it from the top as well as the bottom, asking what happens to communication between brain regions as the state deepens, and the most durable finding is that anaesthesia is better described as a disruption of integration across the cortex than as a general switching-off.

The honest summary is that the subject knows a great deal about where anaesthetics bind and much less about why binding there abolishes awareness. That is not an embarrassment. It is the same gap that separates neurochemistry from psychology everywhere else, and anaesthesia is simply the place where it is most conspicuous.