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For 170 Years, No One's Known How General Anaesthesia Works. We're Finally Getting Close

JACINTA BOWLER
14 JUNE 2020

For well over 100 years hospitals have been putting people under with general anaesthesia to perform routine operations and surgeries. These days, it's used all over the world, thousands of times every day.

 

But although we know that it knocks us out and messes with our consciousness, the actual mechanism behind general anaesthesia was unknown when we first found it, and we still don't have a full explanation.

"That's been a great mystery for about 170 years," Alfred Hospital and Monash University anaesthesia researcher Paul Myles told ScienceAlert. "The straightforward answer is 'no one really knows'."

But that hasn't stopped scientists from coming up with hypotheses for these past 170 years. It's not good enough to just knock people out without understanding what occurs on a deeper biological level, especially given the traumatising experiences of patients who have woken up during surgery.

All the way back in 1847, two researchers proposed the idea of 'lipid theory', where anaesthesia affects the fatty (aka lipid) membranes of cells in the brain to suppress our normal neuronal activity.

Lipid theory slowly lost steam in the proceeding decades in favour of other hypotheses, mostly the idea that certain brain receptors attach to the anaesthetics - the medications used to knock a person out - causing a loss of consciousness.

 

"Researchers around the world have isolated certain receptor types within the brain and sub-cellular mechanisms that create this state of reversible hypnosis or unconsciousness," says Myles.

"We're getting closer to working out how general anaesthetics work and why they work, but there's really a lot more that's not known at this point in time."

However, just in the last year we've seen a number of articles claiming that the mechanism of general anaesthesia has been solved, all in entirely different ways.

While such headlines might have you believe we now have all the answers, things are never that simple. Take the latest paper that started us down this rabbit hole.

The research, published in PNAS, provides an explanation of whether general anaesthetics act directly on ion channels (the 'gates' embedded in cell membranes), or on the membrane in ways we don't yet understand.

The team concluded that although anaesthetics do act on ion channels, there's an in-between step involving lipids.

Now, this is an interesting result, but it's far from the final answer, just like all those other articles before.

 

"The paper highlights some very elegant research that does demonstrate a mechanism of how anaesthetics might affect the brain," Myles told ScienceAlert.

"It's probably part of the story, but it clearly won't be all of the story because it's inconsistent with some other types of research which are much more receptor- or pore-based mechanisms."

This sounds like the research on general anaesthesia is both right and wrong at the same time, which seems unlikely. But there is an ingeniously simple explanation that makes sense of all of this.

With the lipid hypothesis, the idea was that anaesthetics all worked the same way from a molecular perspective. But today, there's a huge number of general anaesthetics used in medicine, all with rather different molecular structures.

It would be one heck of a coincidence if they all worked in exactly the same way.

"That's what's puzzled researchers for a long time, because the anaesthetic drugs (gases or vapours or intravenous drugs) with completely different types of structures, they all seem to create this end state that looks identical," Myles explained.

 

"But they clearly can't be working through a single mechanism because it just wouldn't make sense, there's too many different types of keys going through a single lock."

What's likely is that the end product – the lack of consciousness – is produced by a number of different molecular mechanisms (or locks, to go with the metaphor), and it's not just a one-size-fits-all scenario.

"These locks are probably connected with each other within the cell and you can probably get in and 'unlock' that cell through one of several different mechanisms," says Myles.

"That's why this is still very puzzling. We don't yet know the full extent of what they are, or how that's happening."

So, the headlines that claim researchers have 'solved' how general anaesthesia works aren't entirely wrong. Whether it's about ion channels, special neurons, or a weakening of the synapses in the brain, they're all part of the story. We just don't have the full story just yet.

Thankfully, the more general anaesthesia is investigated, the closer we are getting to a complete answer.

"I've been in specialist anaesthesia practice now for well over 35 years. Back in my earlier career, we simply had no idea at all," Myles told ScienceAlert.

"I think in the last ten years especially, there have been dramatic advances. Literally year by year, we're getting a much better understanding at the cellular level."

Hopefully, we won't have to wait too long until we can safely say that we've truly cracked the case.