New research in mice reveals for the first time that diverse drugs that induce general anesthesia activate a brain circuit that brings on sleep.
The scientists at Duke University in Durham, NC who carried out the study, suggest that the findings will help to develop better drugs that can induce sleep with fewer adverse reactions.
Since 1846, when a dentist and a surgeon carried out the first successful surgical procedure to use anesthesia, a number of general anesthetic drugs have emerged. Yet, until the recent study, it had not been clear how these substances produced a loss of consciousness.
In a Neuron paper, the researchers describe how they discovered the cells in the hypothalamus at the base of the brain.
The cells, which consist mainly of neuroendocrine cells, sit “in and near the supraoptic nucleus” in the hypothalamus and “are persistently and commonly activated by multiple classes of [general anesthetic] drugs,” they write.
Neuroendocrine cells are cells that, as with neurons, or nerve cells, receive signals from the nervous system except that they respond by producing and releasing hormones.
Almost all of the body’s organs contain neuroendocrine cells, and the hormones that they release control many of its functions. The cells have very long projections through which they release the hormones, such as into the bloodstream.
The recent study is important not only because it clarifies how general anesthetics work, but also because it highlights the vital role that hormones play in controlling states that affect the whole brain.
For decades, the standard theory about general anesthesia was that the drugs that induce it inhibit brain activity to the point where the person cannot move or feel pain.
However, in recent times, scientists have come to realize that certain brain circuits are very active during sleep.
Studies have shown, for example, that brain circuits that are active during sleep not only help people to consolidate information that was acquired while they were awake, but they also help them to learn new information while they are asleep.
Senior study author Fan Wang, who is a professor of neurobiology at Duke University School of Medicine, and her team wondered if the same might be true of general anesthesia. What if general anesthetics did more than inhibit brain activity? Could the substances also be activating some circuits?
To investigate this, they induced general anesthesia in mice using diverse drugs that anesthesiologists use to put humans to sleep for operations.
Because they tagged the drugs with molecular markers, the team could trace their destinations in the mice’s brains. The most common destination turned out to be the supraoptic nucleus.
The researchers were surprised by this result. They were not expecting to find that the neuroendocrine system had such an active role in general anesthesia.
They then carried out further experiments using advanced chemical and optical techniques that allowed them to switch this particular group of cells on and off in mice.
Switching the cells on caused the mice to stop moving and fall into a deep, slow-wave sleep that typically occurs during unconsciousness. Switching the cells off stopped the mice from being able to fall asleep.
When they carried out similar tests in mice under general anesthesia, the team found that activating the neuroendocrine cells beforehand made the anesthesia last longer while silencing the cells shortened it.
Study author Dr. Luping Yin, who works in Prof. Wang’s laboratory, says that many drugs for inducing sleep “have troublesome side effects.”
According to a 2005–2010 national survey that the Centers for Disease Control and Prevention (CDC) reported in 2013, around
“If we can find ways to manipulate this neural circuitry, perhaps by targeting hormones or small peptides, then it could lead to the development of better sleeping pills.”
Dr. Luping Yin