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Molecular and neuronal substrates for general anaesthetics

Key Points

  • General anaesthetics are defined by their capacity to produce a state in which surgery can be tolerated without the need for further drugs. They are widely used in both clinical medicine and neuroscience research, but we are only just beginning to understand the molecular mechanisms that underlie their actions.

  • The goals of the anaesthetic state are immobility, unconsciousness and amnesia. It is widely accepted that general anaesthetics cause immobility by depressing spinal neurons, and amnesia and hypnosis by acting on neurons in the brain. However, there is evidence that their spinal actions also influence sedative and hypnotic effects, and conversely, that descending signals from the brain to the spinal cord modify their immobilizing effects.

  • There is a long list of molecular targets, the activity of which is mediated by at least one general anaesthetic, including numerous types of ligand-gated ion channel. In recent years, the GABAA (γ-aminobutyric acid type A) receptor system has attracted considerable attention as a target for general anaesthetics.

  • The great heterogeneity of GABAA receptors has long precluded the attribution of physiological and pharmacological functions to specific subtypes. However, using knock-in point mutations in mice, it has been possible to identify specific GABAA-receptor subtypes that are involved in the actions of the intravenous anaesthetics etomidate and propofol.

  • By integrating results from pharmacological, molecular genetic, functional imaging and electrophysiological studies, we should be able to gain further insights into the mechanisms of anaesthetic action. These insights might also provide avenues for the design of new general anaesthetics with an improved side-effect profile.

Abstract

Although general anaesthesia has been of tremendous importance for the development of surgery, the underlying mechanisms by which this state is achieved are only just beginning to be understood in detail. In this review, we describe the neuronal systems that are thought to be involved in mediating clinically relevant actions of general anaesthetics, and we go on to discuss how the function of individual drug targets, in particular GABAA-receptor subtypes, can be revealed by genetic studies in vivo.

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Figure 1: Structural formulae of anaesthetic agents in current clinical use.
Figure 2: Propofol anaesthesia in humans.
Figure 3: Synaptic and extrasynaptic locations of GABAA receptors.
Figure 4: Amino-acid point mutations in β2(N265S) mice and β3(N265M) mice.
Figure 5: Behavioural responses to intravenous anaesthetics in β3(N265M) and β2(N265S) mice.
Figure 6: Proposed roles of GABAA-receptor subtypes and other targets in etomidate and propofol action.

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Acknowledgements

The authors would like to acknowledge the dedicated work of R. Jurd, M. Arras, S. Lambert and others on the β3(N265M) mouse model discussed in this review. The work was supported by the Swiss National Science Foundation (U.R.), the Deutsche Forschungsgemeinschaft (B.A.) and the Interdisciplinary Center for Clinical Research (IZKF) Tübingen (B.A.).

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Glossary

BENZODIAZEPINES

Pharmacologically active molecules with sedative, anxiolytic and anticonvulsant effects. They act by binding to the GABA receptor and potentiate the response elicited by the transmitter.

OPTICAL ISOMERS

Also known as chiral molecules, optical isomers are molecules that are exact non-superimposable mirror images of one another.

ELECTROENCEPHALOGRAPHY

(EEG). A technique used to measure neural activity by monitoring electrical signals from the brain that reach the scalp. EEG has good temporal resolution but relatively poor spatial resolution.

ALPHA POWER

Rhythmic neural activity with a frequency of 8–12 Hz.

BETA POWER

Rhythmic neural activity with a frequency of 12–25 Hz.

THETA POWER

Rhythmic neural activity with a frequency of 4–12 Hz.

DELTA POWER

Rhythmic neural activity with a frequency of 1–4 Hz that is characteristic of stage III and IV non-rapid eye movement sleep (also known as slow-wave sleep).

TONIC

Physiological events that occur in a sustained manner, unlike phasic events, which occur only transiently with intervening periods of inactivity.

GAMMA OSCILLATIONS

Rhythmic neural activity with a frequency of 25–70 Hz.

EC50

The concentration of an agent that provides a half-maximal activation of a target in vitro.

IC50

The concentration of an agent that provides a half-maximal inhibition of a target in vitro.

TAIL CLAMP/WITHDRAWAL ASSAY

An assay in which motor activity is measured in response to a tail-clamp stimulus.

KNOCK-IN TRANSGENIC APPROACH

The insertion of a mutant gene at the exact site of the genome where the corresponding wild-type gene is located. This approach is used to ensure that the effect of the mutant gene is not affected by the activity of the endogenous locus.

PRE-PULSE INHIBITION

The ability of a weak pre-stimulus to inhibit the response to a stronger stimulus when the two stimuli are presented in quick succession.

TETRODOTOXIN

A potent marine neurotoxin that blocks voltage-gated sodium channels. Tetrodotoxin was originally isolated from the tetraodon pufferfish, and contains a positively charged guanidinium group and a pyrimidine ring.

PLATEAU POTENTIAL

A stable membrane potential that is more depolarized than the resting potential. The term derives from the 'plateau phase' of the action potential.

HINDLIMB-WITHDRAWAL REFLEX

If a mouse's hindlimbs are pulled back, the animal finds this painful, and it reflexively draws the limbs in towards the body.

PURKINJE CELLS

Inhibitory neurons in the cerebellum that use GABA as their neurotransmitter. Their cell bodies are situated beneath the molecular layer, and their dendrites branch extensively in this layer. Their axons project into the underlying white matter, and they provide the only output from the cerebellar cortex.

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Rudolph, U., Antkowiak, B. Molecular and neuronal substrates for general anaesthetics. Nat Rev Neurosci 5, 709–720 (2004). https://doi.org/10.1038/nrn1496

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