Unravelling how local anaesthetics work

The discovery of the exact mechanism by which pain-relief drugs work may lead to new pain treatments.

Although local anaesthetics have been used in medicine for more than 100 years, the precise way in which they prevent nerve cells from signalling pain to the brain has not been understood.

Dr Ben Corry and Lewis Martin from the Australian National University developed a detailed computer model that revealed how benzocaine, a local anaesthetic, and phenytoin, an anti-epilepsy drug, enter into nerve cells and prevent pain signals being transmitted to the brain.

Electrical impulses, such as pain signals, propagate along nerve fibres via voltage-gated ion channels that alternate the ion gradient across the nerve cell wall. Local anaesthetics inhibit this depolarisation of nerve cells by interfering with the ion channel, preventing the electrical signal from being transmitted.

In this study, the researchers simulated the route benzocaine took to enter into the bacterial voltage gated sodium channel, NavAb, on the National Computational Infrastructure’s supercomputer. They found that its final binding site was inside the sodium gateway protein, which it blocked, preventing the nerve signal from being transmitted.

This knowledge of precisely how the drug molecules attach to proteins in the nerve cell gives a springboard for redesigning drugs without the side effects that current drugs bring with them.

“By understanding how the current range of drugs work we can best design the next generation, to better treat conditions such as chronic pain, epilepsy and cardiac arrhythmia,” said Dr Corry.

Drugs that block sodium channels are also used to treat nerve-signal disorders such as epilepsy or heart arrhythmia. However, current drugs target the nine known sodium channels indiscriminately throughout the body, which can lead to side effects.

The work opens up the possibility for developing new drugs designed to selectively target the subtly different proteins in specific locations of the body, such as the heart or brain.

Dr Corry also plans to investigate the development of antibiotics based on this approach.

The work has been published in PLOS Computational Biology.