Posted on by Dr. Francis Collins
General anesthesia has been around since the 1840s, when most people still traveled by horse and buggy. Yet, in this age of jet planes and electric cars, there are still many unknowns about how general anesthesia works.
The prevailing view has long been that general anesthesia exerts a sedative effect that puts us under, along with a pain-relieving effect that works by temporarily shutting down transmission of sensations from other parts of the body to the brain. Now, researchers have discovered that, at least in mice, some types of general anesthesia may actually activate a specialized area of the brain—findings that not only may provide new insights into anesthesia, but may enhance our understanding of sleep.
In a recent study in the journal Neuron, the NIH-supported lab of Fan Wang at Duke University, Durham, NC, used general anesthesia as a tool to learn more about mammalian brain activity. When they placed mice under multiple classes of general anesthesia, a cluster of neurons were activated in the brain’s hypothalamus that produce slow, oscillating waves similar to those observed in the brains of mice that were sleeping deeply. When these neurons were later artificially deactivated, the effects of general anesthesia were shortened. Experiments in sleeping mice also showed that similar deactivation disrupts natural sleep. The discovery suggests there may be a neural pathway in the mammalian brain that is shared by general anesthesia and natural sleep, perhaps opening the door to new drugs for anesthesia, pain management, and sleep disorders .
Specifically, Wang’s group is focused on a part of the hypothalamus called the supraoptic nucleus (SON), which consists of about 3,000 neurons. These neurons are wired into the brain’s neuroendocrine system, a vast regulatory system between brain and body. Each SON neuron has two arms: one extends to the base of the brain, where it triggers the pituitary gland to release hormones; the other directly releases peptide hormones into the general circulation.
It’s not altogether surprising that the hypothalamus would be involved regulating sleep. Previous work had indicated that another part of the hypothalamus might serve as an on-off switch between wakefulness and sleep . The neurons also secrete neuropeptides, such as galanin and GABA. that inhibit areas of the brainstem involved in wakefulness.
But what most fascinated Wang is that her experiments found that SOS cells fire constantly in mice that have been kept awake past their normal bedtime, but stop firing once the animals are allowed to sleep. This prompted her team to turn its attention to the 80 percent of SON neurons that secrete the hormones dynorphin and vasopressin, which are secreted in the general circulation and send a wide range of signals to organs throughout the body.
Though mice are not humans and much more work remains to be done, Wang says her data raise the possibility that sleep, like hunger, may be regulated by a feedback loop of hormones, traveling from brain to other body parts and back. As proposed, the SON cells secrete hormones into the body during periods of wakefulness. As the level of the secreted messengers build up, the body signals to the brain that it’s tired, prompting the SOS neurons to activate a different program, sending signals that tell other parts of the brain to go to sleep.
Discovering a homeostatic sleep mechanism certainly wasn’t what surgeon William T. G. Morton had in mind when he first demonstrated the concept of general anesthesia in the 19th Century. Yet more than 175 years later, Morton’s major clinical advance is now yielding unexpected benefits for basic neuroscience research, providing yet another example of how one never knows where biomedical exploration may take us.
 A Common Neuroendocrine Substrate for Diverse General Anesthetics and Sleep. Jiang-Xie LF, Yin L, Zhao S, Prevosto V, Han BX, Dzirasa K, Wang F. Neuron. 2019 Apr 18. pii: S0896-6273(19)30296-X.
 Activation of ventrolateral preoptic neurons during sleep. Sherin JE, Shiromani PJ, McCarley RW, Saper CB. Science. 1996 Jan 12;271(5246):216-219.
Anesthesia (National Institute of General Medical Sciences/NIH)
History of Anesthesia (Wood Library Museum of Anesthesiology, Schaumburg, IL)
Brain Basics: Understanding Sleep (National Institute of Neurological Disorders and Stroke/NIH)
Fan Wang (Duke University School of Medicine, Durham, NC)
NIH Support: National Institute of Mental Health