How Does General Anaesthetic Work?

Typically used in surgeries and serious medical procedures, general anaesthetic uses a cocktail of medications to force patients into a sleep-like state and inhibit the brain’s ability to feel pain. Now, new research from the Okinawa Institute of Science and Technology (OIST) Graduate University reveals how general anaesthetic works.

Dulling synapses to induce anaesthesia

Working with mice and rats, the team explored how a general anaesthetic known as isoflurane hinders the transmission of electrical signals between neurons. Usually, these transmissions take place at synapses, the name for the junctions that divide nerve cells and transmit electrical impulses. Weakening electrical signals transmission dulls high frequency brain activity and brings on a state of unconsciousness. The findings were published in the Journal of Neuroscience, with commentary from Professor Tomoyuki Takahashi.

“Importantly, we found that isoflurane did not block the transmission of all electrical signals equally; the anaesthetic had the strongest effect on higher frequency impulses that are required for functions such as cognition or movement, whilst it had minimal effect on low frequency impulses that control life-supporting functions, such as breathing," says Takahashi, head of the Cellular and Molecular Synaptic Function Unit at OIST. "This explains how isoflurane is able to cause anaesthesia, by preferentially blocking the high frequency signals."

Investigating the calyx of Held

The team homed in on a large synapse known as the calyx of Held, which mediates high-frequency electrical signals. After sending the calyx of Held electrical signals at various frequencies, the team analysed the action potentials triggered in the postsynaptic neuron, which receives the neurotransmitter after it’s been transmitted through the synapse. They observed that higher frequency electrical signals increased the capacity of isoflurane to block transmission, explaining why it’s so effective at forcing the body into an unconscious and unresponsive state.

The importance of high frequency signals

Determined to pinpoint the mechanisms that allow isoflurane to dull synapses, the team investigated the impact the general anaesthetic has on calcium ion channels, which support the function of synapses.

“Crucially, we found that this block only had a major effect on high frequency signals, suggesting that this block on exocytic machinery is the key to isoflurane's anesthetising effect," says Takahashi. “Now that we have established techniques of manipulating and deciphering presynaptic mechanisms, we are ready to apply these techniques to tougher questions, such as presynaptic mechanisms underlying symptoms of neurodegenerative diseases," he adds. "That will be our next challenge."

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