How do general anaesthetics work? Scientists may have finally found the answer

If you’ve ever heard of propofol it’s most likely because it was one of several drugs responsible for Michael Jackson’s death in 2009.

Either that, or because it’s widely used in one of the most common medical procedures worldwide, as a general anaesthetic. Despite its prevalence, however, we’ve never truly understood how it works.

Until now.

 Thanks to work by Associate Professor Bruno van Swinderen and his team of researchers at the University of Queensland, Australia, we now understand that beyond simply sending you to sleep, propofol is doing something much more significant to your brain.

After looking at the effects of propafol on synaptic release, the mechanism by which nerve cells communicate with each other, Professor van Swinderen and his team made a groundbreaking discovery.

“We know from previous research that general anaesthetics including propofol act on sleep systems in the brain, much like a sleeping pill…but our study found that propofol also disrupts presynaptic mechanisms, probably affecting communication between neurons across the entire brain in a systematic way that differs from just being asleep. In this way it is very different than a sleeping pill,” said van Swinderen.

The research paper’s first author, PhD student Adekunle Bademosi goes into more detail, explaining exactly how the drug stops signals being passed between nerve cells:

“We found that propofol restricts the movement of a key protein – syntaxin1A – required at the synapses of all neurons. This restriction leads to decreased communication between neurons in the brain”.

A representation of thousands of tracked syntaxin1A molecules in a neuron exposed to propofol (Image credit: Associate Professor Bruno van Swinderen)

So what does this mean, for you and me?

Well, it’s obviously a significant development in terms of understanding exactly how general anesthetics work and, in particular, it goes some way to explaining why people can be groggy and confused about their whereabouts when they come round after an operation. After all, the drug has essentially shut down most activity within the brain. Beyond this, it might also help to shed light on why some groups are intolerant to general anaesthetic.

“The discovery has implications for people whose brain connectivity is vulnerable, for example in children whose brains are still developing or for people with Alzheimer’s or Parkinson’s disease,” continued van Swinderen.

“It has never been understood why general anaesthesia is sometimes problematic for the very young and the old. This newly discovered mechanism may be a reason.”

The associate professor added that in order to determine if general anaesthetics have lasting effects in these vulnerable groups of people, researchers would need to use “model systems” like rats and flies to experiment with the likely mechanisms involved.

When asked what the impact of his team’s findings on the future of general anesthetics might be, the researcher told Alphr: “Practitioners have settled on effective and safe drugs such as propofol and etomidate. We think these drugs ‘work’ as general anaesthetics because they indeed first put you to sleep, at lower dose, before showing these presynaptic effects.

“The sleep-related effect of these drugs is fairly well understood. However, if propofol indeed restricts syntaxin1a mobility in a trillion synapses across the brain, then that is something that should be considered with regard to potential side-effects.

“If this mechanism is key to general anaesthesia, perhaps some other drugs (or combinations of drugs) do this in a safer way. Or maybe we have empirically already found the best drugs, after 180 years of trial and error. But understanding the mechanism is important.”