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General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal

Key Points

  • It is now accepted that general anaesthetics act at specific molecular targets, and a relatively small number of likely ion channels and receptors have been identified — the γ-aminobutyric acid type A receptor, two-pore-domain K+ channels and N-methyl-D-aspartate receptors top the list. Anaesthetics probably affect these channels by selectively binding to specific conformational states.

  • Many anaesthetic determinants on these targets have been investigated, partly in the hope that they could be introduced as 'silent' mutations in animals to test the in vivo significance of the putative target; this approach is beginning to yield exciting results.

  • Focus in this field of research is gradually shifting to the question of how effects on these targets might translate into effects in the intact animal, and one possibility that has emerged is that anaesthetic-induced loss of consciousness and deep sleep might have common neuronal mechanisms.

  • Support for this idea comes from human imaging studies, which have revealed striking similarities between the two states. This similarity is due, in large part, to the thalamic deactivation that occurs during deep sleep and during anaesthetic-induced loss of consciousness.

  • Further evidence comes from in vitro studies on the neuronal pathways that underlie behavioural arousal and those that are responsible for the initiation and maintenance of sleep.

  • Current evidence suggests that anaesthetics might induce reversible loss of consciousness by acting on arousal and sleep pathways that involve both the thalamus and the hypothalamus.

Abstract

The mechanisms through which general anaesthetics, an extremely diverse group of drugs, cause reversible loss of consciousness have been a long-standing mystery. Gradually, a relatively small number of important molecular targets have emerged, and how these drugs act at the molecular level is becoming clearer. Finding the link between these molecular studies and anaesthetic-induced loss of consciousness presents an enormous challenge, but comparisons with the features of natural sleep are helping us to understand how these drugs work and the neuronal pathways that they affect. Recent work suggests that the thalamus and the neuronal networks that regulate its activity are the key to understanding how anaesthetics cause loss of consciousness.

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Figure 1: Loss of consciousness in humans occurs over a very narrow range of anaesthetic concentrations and correlates with loss of the righting reflex in rodents.
Figure 2: Three key molecular targets and some known determinants of their anaesthetic sensitivities.
Figure 3: Functional brain imaging reveals similarities between anaesthetic-induced loss of consciousness and deep natural sleep.
Figure 4: Thalamic oscillations.

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Acknowledgements

I thank S. Brickley and A. Zecharia for many helpful and stimulating discussions during the writing of this Review and their assistance in the preparation of the figures, P. Brick and S. Curry for help with the crystallographic images and C. Robledo for providing the EEG data in figure 4. I also thank the Medical Research Council UK for support.

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Free aqueous concentrations for human loss of consciousness and rodent loss of righting reflex* (PDF 178 kb)

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Glossary

Tonic inhibition

Background inhibition resulting from persistent low-level activation of GABAA receptors. The main component of this current is thought to be mediated by extrasynaptic receptors with relatively high affinities for GABA.

Phasic inhibition

Inhibition resulting from the transient release of a high concentration of GABA from presynaptic terminals.

Sulphydryl reagents

Various chemical reagents that selectively react with SH groups and which are hence used to label the sulphur-containing amino acids (cysteine and methionine).

Photoreactive anaesthetics

Modified anaesthetics that contain groups (such as diazirines) that are converted into reactive species following stimulation by light; they are used to selectively and irreversibly label an anaesthetic-binding site.

Righting reflex

The postural response of an animal when placed on its back or side to reorient itself such that its paws or feet are oriented towards the ground.

Blood–brain barrier

A layer of tightly apposed endothelial cells that lines blood capillaries and forms a barrier to the diffusion of substances from the blood into the brain. Apolar molecules, such as general anaesthetics, however, readily permeate this barrier.

Positron-emission tomography

(PET). A technique that uses positron emitters, such as 15O, to measure local changes in cerebral blood flow, which can be interpreted as reflecting local neuronal activity.

Somatosensory-evoked potentials

Electrical signals generated by the nervous system following a mechanical or, more usually, an electrical stimulation in the periphery that reflect sequential activation of neural structures along the somatosensory pathways.

Inhibitory shunt

Inhibition of excitatory inputs owing to an increase in neuronal membrane conductance.

Encephalitis lethargica

A condition that affected millions of people in the 1920s and which was first described by Constantin von Economo. It was characterized by a high fever, profound lethargy and many other neurological changes that, in extreme cases, led to irreversible coma. It was sometimes described as 'sleeping sickness'.

c-fos

An immediate-early-gene product that can be upregulated by various cellular stimuli, including neuronal excitability. It is sometimes used as a surrogate measure of neuronal activity.

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Franks, N. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci 9, 370–386 (2008). https://doi.org/10.1038/nrn2372

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