How does anesthesia work? Experts still have questions.

The age of anesthesia began in 1846, when a man named Edward Abbott came to Massachusetts General Hospital with a painful growth under his jaw. Dental surgeon William Thomas Green Morton saw the case as the perfect opportunity to test his anesthetic breathing apparatus in the hospital’s amphitheater. In front of a packed crowd of surgeons, Morton asked Abbott to breathe in the fumes of a sweet-smelling liquid, known as ether, contained inside a small glass sphere. Within minutes of inhaling, Abbott was unconscious. 

While doctors have significantly refined their techniques over the subsequent 150 years—ether made patients throw up and was flammable enough to cause mid-surgery explosions—there are still outstanding questions about how anesthesia works. 

How anesthetics slow the brain

That’s not to say there hasn’t been progress. Doctors now deliver safer anesthetics in more controlled ways, and there have been huge strides made in our understanding of how these drugs work at a molecular level. “Historically, it was thought these were very non-specific compounds,” says Nick Franks, a professor of biophysics and anesthetics at Imperial College London. Now, he adds, researchers have identified the specific brain molecules that anesthesia tweaks to alter our consciousness. 

Low doses of most anesthetics, says Franks, work by affecting our brain cells’ receptors. These receptors are like ports that shuttle molecules into and out of these cells. Several anesthetics, including propofol, thiopental, and isoflurane, increase molecular traffic through a specific “port” known as the GABA receptor. This receptor normally gives passage to gamma-aminobutyric acid (GABA), an important molecule that inhibits brain activity. By increasing activity at the GABA receptor, anesthetics further slow the brain. 

Franks, alongside his colleague Bill Wisden, is especially interested in the anesthetic dexmedetomidine, usually known as Dex. This drug blocks signaling through receptors in the brainstem for the molecule norepinephrine, which excites our brain. As the brainstem is crucial for maintaining consciousness, blocking these receptors sedates patients. 

What’s the difference between sleep and anesthesia?

Where our certainty about anesthesia breaks down is in linking molecular changes to specific neural pathways, or in understanding the subjective experiences of a sleep-like state. Research is further complicated by the range of different effects brought on by anesthetics. Dex, for example, produces a state “like non-REM sleep,” says Wisden. Patients can be briefly roused—for example, to ask them to roll over or change a dressing—before falling unconscious again. 

“When you look at the electrical waves that happen in sleep and when you get given this particular sedative, they look very similar,” Wisden adds. Other anesthetics, like propofol, have different effects. At higher doses, propofol essentially stops all brain activity, except that required for basic survival. 

Sleep-mimicking anesthetics, like Dex, don’t produce a perfect imitation. Physiological changes that occur when we sleep, such as fluctuations in body temperature and heart rate, also occur under Dex, but more strongly—which is why medical professionals must administer the drug in a hospital setting. If natural sleep is attained by carefully dialing down our consciousness across several different parameters, anesthesia involves a more aggressive turn of these dials.

Why we need better anesthetics

General anesthesia is now very safe, with deaths linked to anesthesia occurring less than one in every 100,000 uses. However, anesthesia can still be improved—complications related to anesthesia-induced body temperature changes remain a concern. If we can better understand anesthesia and create drugs that mimic natural rest more effectively, there could be huge benefits for patients. “After a good night’s sleep, you feel better,” says Franks. “You generally do not feel like that after an anesthetic, although it’s confounded by whatever procedure or surgery you may have had.” 

Although they aren’t interested in drug development, Franks and Wisden say Dex would be the “ideal” drug for exploring how to make an anesthetic that helps you feel rested, as it most closely mimics natural sleep. Some studies have even suggested the drug improves sleep quality in post-operative patients. Even if how Dex works on a molecular level is clear, what it does when it affects all the receptors in our brain—and even where those receptors are—remains a mystery.

As our tools for mapping the brain and its activity continue to improve, we will come closer to developing anesthetics that feel more akin to a good night’s rest. 

This story is part of Popular Science’s Ask Us Anything series, where we answer your most outlandish, mind-burning questions, from the ordinary to the off-the-wall. Have something you’ve always wanted to know? Ask us.