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Sleep and sedation controlled in same brain centre, say scientists

26.08.2002

Undergoing anaesthesia may be more like falling asleep than we once thought, according to new research from Imperial College London and Harvard Medical School, USA.

Researchers report today in the journal Nature Neuroscience how two of the most widely used anaesthetics, pentobarbital and propofol induce sleep by mimicking the natural process of falling into a deep sleep.

Using behavioural studies and molecular imaging techniques in rats, the team of basic scientists and clinicians found that the sleep-inducing action of anaesthetics is localised to a small area of the brain, the tuberomammillary nucleus (TMN), part of the hypothalamic region that controls other fundamental processes such as breathing and temperature regulation.

The team showed that the anaesthetics produce their sedative effect by locking on to a specific type of neurotransmitter receptor in the TMN called GABA-A.

GABA-A receptors have an inhibitory action, hence when anaesthetic molecules bind to them they stop the nerve cells from sending electrical signals to other neurons.

"The sleep-inducing action of general anaesthetics occurs by hijacking one pathway in the brain responsible for promoting deep sleep," said Professor Nick Franks of Imperial College London.

"The TMN region of the brain is part of a key switching mechanism in the sleep/wake cycle. When stimulated, it sends excitatory signals to other parts of the brain telling the body to be awake. TMN neurons are pharmacologically inhibited by the negative action of the anaesthetics binding to the GABA-A receptor - leading to a sleep induced state," said Professor Franks.

"Although not all anaesthetics exert their sedative effect using GABA-A receptors, the research is significant because it indicates that the sleep-inducing effect of anaesthetics acts on specific areas of the brain," he added.

Professor Mervyn Maze, Head of the Department of Anaesthetics and Intensive Care at Imperial College London and senior author of the study said that their new understanding of how anaesthetics induce sleep could lead to new anaesthetics providing a better recovery for patients.

"Individuals need a prolonged period of deep sleep to gain its restorative benefits. Patients recovering from surgery and those in intensive care often suffer from sleep-deprivation. Our research might lead to the design of anaesthetics that mimic non-REM sleep more accurately, reducing post-operative fatigue," said Professor Maze.

The research was supported by the Medical Research Council (UK), the Westminster Medical Trust (UK) and the National Institutes of Health (USA).

1. Title: The Sedative component of anesthesia is mediated by GABA-A
receptors in an endogenous sleep pathway.
Authors: Nelson LE (1,2), Guo TZ (1), Lu J (3), Saper CB (3), Franks NP
(1,2), Maze M (1,2).

(1) Department of Anesthetics and Intensive Care, Chelsea and
Westminster Hospital, Imperial College London.
(2) Biophysics Section, Blackett Laboratory, Department of Biological
Sciences, Imperial College London.
(3) Department of Neurology, Harvard Medical School, Beth Israel
Deaconess Medical Centre, Boston, Massacusetts.

2. Most neurons transmit electrical signals between cells of the nervous
system by releasing chemicals known as neurotransmitters to receptors on the
receiving cell. The action of the neurotransmitter binding to the receptor
either inhibits, or excites the nerve cell to fire an electrical pulse.

3. Consistently rated in the top three UK university institutions, Imperial
College London is a world leading science-based university whose reputation
for excellence in teaching and research attracts students (10,000) and staff
(5,000) of the highest international quality. Innovative research at the
College explores the interface between science, medicine, engineering and
management and delivers practical solutions, which enhance the quality of
life and the environment - underpinned by a dynamic enterprise culture.