We Now Know More About How General Anesthesia Works

The First Operation Under Ether (Robert C. Hinckley, 1882–1893). Wikimedia Commons

If you have ever received general anesthesia, you likely witnessed that doctors take the process of putting a patient under very seriously. This is because there are a lot of risks associated with the drugs that induce this state, and also because we still don’t fully understand how it works – 172 years after its invention.

Now, researchers from the Queensland Brain Institute in Australia have helped unravel the effects of a common intravenous anesthetic called propofol.

Previous studies on the drug have revealed that propofol increases the actions of the GABA inhibitory system. GABA is a neurotransmitter that binds to receptors on cells throughout the central and peripheral nervous systems.

When bound, GABA prevents the membrane from depolarizing and sending an electrical signal to its neighboring cells. This pathway is responsible for blocking communication between neurons in certain areas of your brain when you’re asleep or under sedation. GABA also induces a relaxed muscle tone during unconsciousness that prevents you from springing out of bed and acting out your dreams or flailing on the operating table.

The current study, published in Cell Reports, used samples of nerve cells from rats and fruit flies and an advanced, single-molecule tracking microscope to show that propofol actually interferes with the release of all neurotransmitters by slowing the actions of a protein called syntaxin1A.

Syntaxin1A is essential to the process of moving neurotransmitter molecules stored inside neurons through the membrane, so that they can be released into the space between one cell and another. Seemingly all organisms with nervous systems rely on syntaxin1A for this function.

An artistic rendering of neurotransmitter release in the synapse between neurons. Andrii Vodolazhskyi/Shutterstock

"We found that propofol restricts the movement of [syntaxin1A], required at the synapses of all neurons," said lead author and PhD student Adekunle Bademosi in a statement. "This restriction leads to decreased communication between neurons in the brain."

By slowing neurotransmitter activity, propofol essentially induces a cerebral "traffic jam". Messages from one area of the brain can’t get to another, preventing you from reaching a state of consciousness.

“With most animal brains comprising anywhere between millions and trillions of synapses, it seems plausible that normal brain functions would be compromised if syntaxin1A mobility became globally restricted across a variety of synapses following exposure to general anesthetics,” the authors state in their conclusion.

They also found that another common anesthetic agent called etomidate had the same effect on syntaxin1A.

The findings help further differentiate the mechanisms underlying varying states of unconsciousness and may explain why general anesthesia is particularly dangerous to certain groups of patients.

An anesthetized patient lies on an operating table with a blood oxygen monitor. UfaBizPhoto/Shutterstock

“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,” said team leader Bruno van Swinderen.

Future research will be necessary to unpack how exactly propofol and etomidate disrupt syntaxin1A, but until then, every bit of insight into this medical puzzle is worth savoring.

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