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

  title={General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal},
  author={Nicholas P. Franks},
  journal={Nature Reviews Neuroscience},
  • N. Franks
  • Published 1 May 2008
  • Biology
  • Nature Reviews Neuroscience
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… 

General anesthesia and ascending arousal pathways.

The authors take an in vivo approach, studying the effects of histamine and histamine receptor antagonists on cortical (and hippocampal) recordings from anesthetized rats, and show that histamine infusion into this region speeds up emergence from isoflurane anesthesia.

Sleep and general anesthesia

There is growing evidence in this review that modulating wake-active neurotransmitter release can impact on anesthesia, supporting the idea that this point of convergence is at the level of the brain arousal systems.

Sleep and Anesthesia Interactions: A Pharmacological Appraisal

This review will highlight the relevant sleep architecture and systems and focus on studies over the past few years that implicate these sleep-related structures as targets of anesthetics, highlighting a promising area of investigation regarding the mechanisms of action.

Linking sleep and general anesthesia mechanisms: this is no walkover.

The link between physiological sleep and general anesthesia is defined and the observed functional modifications of brain activity during anesthesia and the known biochemical targets of hypnotic anesthetic agents are determined.

Neurochemical Modulators of Sleep and Anesthetic States

This chapter focuses on intravenous and volatile anesthetics that have been shown to alter endogenous neurotransmitters known to regulate states of Consciousness and Sleep-Related Neurotransmitters.

Anaesthesia and sleep

The mechanisms regulating the control of consciousness in both spontaneous sleep–wake behaviour and general anaesthesia remain poorly understood and need to be elucidated to build a unifying mechanism of consciousness control.

Mechanisms of general anesthetic action: Focus on the cellular network

Several lines of evidence suggest that disruption in brain network connectivity is important for anaesthesia-induced loss of consciousness and this is discussed in relation to morphological changes.

The Neural Circuits Underlying General Anesthesia and Sleep.

Modern neuroscience techniques that enable the manipulation of specific neural circuits have led to new insights into the neural circuitry underlying general anesthesia and sleep, and it is likely that each class of anesthetic drugs produces a distinct combination of subcortical and cortical effects that lead to unconsciousness.



Molecular and neuronal substrates for general anaesthetics

The neuronal systems that are thought to be involved in mediating clinically relevant actions of general anaesthetics are described and how the function of individual drug targets, in particular GABAA-receptor subtypes, can be revealed by genetic studies in vivo is discussed.

Sleep, Anesthesiology, and the Neurobiology of Arousal State Control

This review considers 40 yr of research regarding the cellular and molecular mechanisms contributing to arousal state control and provides overwhelming support for the view that decrements in vigilance can negatively impact performance.

Molecular and cellular mechanisms of general anaesthesia

It is now clear that anaesthetics act directly on proteins rather than on lipids, with potentiation of postsynaptic inhibitory channel activity best fitting the pharmacological profile observed in general anaesthesia.

An essential role for orexins in emergence from general anesthesia

It is concluded that there are important differences in the neural substrates mediating induction and emergence that support the concept that emergence depends, in part, on recruitment and stabilization of wake-active regions of brain.

Volatile general anaesthetics activate a novel neuronal K+ current

It is reported that amongst a group of apparently identical molluscan neurons having endogenous firing activity, a single cell displays an unusual sensitivity to volatile agents (which, at surgical levels, completely inhibit its activity); it is shown that this sensitivity is due to a novel anaesthetic-activated K+ current, which is found in the sensitive cell but not in the surrounding insensitive cells.

Neocortex is the major target of sedative concentrations of volatile anaesthetics: strong depression of firing rates and increase of GABAA receptor‐mediated inhibition

These findings challenge the notion of predominantly subcortical effects of volatile anaesthetics and suggest that intracortical targets, among them neocortical GABAA receptors, mediate the sedative and hypnotic properties of volatile Anaesthetics.

Neural pathways associated with loss of consciousness caused by intracerebral microinjection of GABAA‐active anesthetics

It is hypothesize that barbiturate anesthetics and related agents microinjected into the MPTA enhance the inhibitory response of local GABAA‐R‐bearing neurons to endogenous GABA released at baseline during wakefulness, ultimately leading to loss of consciousness.

Distinct molecular targets for the central respiratory and cardiac actions of the general anesthetics etomidate and propofol

Results show that both immobilization and respiratory depression are mediated by β3‐containing GABAA receptors, hypnosis by bothβ3‐and β2‐ containing GAB AA receptors, while the hypothermic, cardiac depressant, and sedative actions are largely independent of β3-containing GabAA receptors.

What can in vivo electrophysiology in animal models tell us about mechanisms of anaesthesia?

Animal experiments can be designed to take the questions about anaesthetic actions to the level of the living organism, as it is controversial which of the many effects of anaesthetics demonstrated in vitro are important for producing relevant in vivo effects.

Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors

Observations support the idea that anaesthetics exert a specific effect on these ion-channel proteins, and allow for the future testing of specific hypotheses of the action of anaesthetic action.