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It's safe to say that general anesthesia has made modern medicine possible. So it might surprise you to hear that even though doctors have been using general anesthesia for nearly 200 years, they haven't known exactly how it works in the brain to temporarily shut it down.

We know that anesthesia doesn't just put someone to sleep. It's closer to a temporary coma, where you don't respond to pain or other stimuli. Your anesthesiologist can keep you in that state, and reverse it when it's time to wake up.

But what's actually happening in your brain while that goes on has been a mystery... until now. There have been two main hypotheses for how anesthesia works on a molecular level. The first, called the lipid hypothesis, has been around since the turn of the 20th century.

That's when scientists observed that the potency of some anesthetics directly correlates with their ability to dissolve in oils. Our cell membranes are made of oily molecules called lipids. And there are several anesthetic drugs that are all oil-soluble.

So it made sense that an affinity for our cell membranes could be the key to how they worked. But the lipid hypothesis started to lose support after the membrane protein hypothesis gained traction in the 1980s. That's when evidence was coming to light that anesthetics could bind to proteins in the membranes of nerve cells, as opposed to interacting with the membranes themselves.

We've managed to identify several proteins that bind with different anesthetics. And protein binding is how most drugs work. Still, that didn't explain what those anesthetics were doing after they were bound.

But a June 2020 study has revealed a major clue into the mechanism of general anesthesia — and in this case, it's actually consistent with the lipid hypothesis. The study was specifically interested in inhaled anesthetics, rather than injected ones. It demonstrated that inhaled anesthetics disrupt lipid rafts in nerve cells.

These are clusters of lipids that form part of the cell membranes of neurons. They seem to play a key role in the central nervous system. Studies suggest that lipid rafts are more tightly packed than the surrounding cellular membrane, and have a slightly different chemical composition.

The researchers used a super high-tech microscope to show lipid rafts expanding and bursting apart like billiard balls in response to anesthetics. When the rafts bust apart, they spill their contents, including an enzyme called PLD2. Once on the loose, the researchers showed,.

PLD2 heads over to a protein called TREK-1. Once there, it binds to TREK-1 and switches it on. That causes it to open up and churn out positively-charged potassium.

Nerve cells need a certain balance of charged particles, including potassium, to fire and do their jobs. The potassium increases the charge of the nerve enough for it to malfunction, inhibiting the firing of neurons. In other words, you're out like a light.

Or so it went in fruit flies! To image the rafts, the researchers used an advanced microscope that can pick out single molecules. Lipid rafts are smaller than what you can normally image using visible light — a limitation called the diffraction barrier.

This technology finally provided enough resolution to work around that barrier and actually visualize the lipid rafts. Which is how they were finally able to propose an answer to such an old question. We're still not sure why this mechanism exists — obviously it didn't evolve so surgeons could use anesthesia.

Further research ought to shed light on why our neurons do this... billiard ball lipid raft thing. It could also help scientists better understand how neurons work, and may reveal new treatments for nervous system disorders. So we finally have an idea for how some kinds of general anesthesia work — after over a hundred years of trying to figure it out.

Which is pretty cool, and reassuring if you're headed in for surgery sometime soon. Thanks for watching this episode of SciShow, and thanks to our patrons, who help us bring mind-blowing facts like this one to an Internet near you. If you'd like to get involved and help support our family of channels, check out patreon.com/scishow. [♪ OUTRO].