Local anaesthetics have been used in the clinic for well over a century. Cocaine was the first drug to be used to block sensory nerves, but was fairly quickly superseded by a number of synthetic alternatives that don't have the pesky side effects of inducing euphoria or being highly addictive. Local anaesthetics work by blocking the flow of sodium ions across neuronal cell membranes, blocking the transmission of electrical signals. Unfortunately, they can be fairly long lasting and not particularly selective, as you might have noticed if you've ever attempted to drink something following a visit to the dentist.

A new option has been described in Nature Methods, developed by a group of researchers at UC Berkeley, the University of Munich and the University of Bordeaux. The group describes a novel local anaesthetic that can be switched on and off using different wavelengths of light, potentially allowing much finer control of exactly which nerves it blocks.

The molecule, called quaternary ammonium-azobenze-quaternary ammonium (QAQ), resembles lidocaine, a commonly used local anesthetic. QAQ comes in two forms, cis and trans. In its trans form, the molecule is a straight chain, but 380 nm light converts it to the cis form, which is bent like an L. In the dark, QAQ slowly reverts back to the trans form; however this can also be achieved much more rapidly by illumination with 500 nm light.

Once inside a cell, in its trans form QAQ blocks many different ion channels, whereas its cis form is inactive.

The difficulty though, is getting QAQ into a cell in the first place. It's a fairly large molecule, and doesn't normally cross cell membranes. To demonstrate the effectiveness of the photoswitching, the researchers actually had to inject it into the cytoplasm of the cells they were testing. One might think that would severely limit its usefulness, but in fact this lack of membrane permeability actually gives QAQ the potential to be very selective as a local anaesthetic.

Pain-sensing (nociceptive) neurons contain a great many ion channels that are activated by noxious stimuli. One of the ion channel found mainly in nociceptive neurons is called TRPV1, which is activated by capsaicin (a chemical from hot peppers), heat, and various other inflammatory mediators.

When activated for a prolonged period of time, TRPV1 receptors dilate, and the pore in the ion channel becomes large enough for bigger molecules to pass through into the cell, including QAQ. The relative absence of TRPV1 on other kinds of sensory nerves means that it's possible to get the drug selectively into nerve cells that are actively sensing pain, where it can then be turned on and off with different wavelengths of light.

The researchers propose that QAQ could be used both clincally as a targeted analgesic, as well as a research tool. In the past few years, there has been a lot of research in a field called optogenetics, where light is used to alter nerve cell activity. The authors propose that the tools and techniques developed to allow optogenetics research can be adapted to use with QAQ, allowing relatively fine control, switching off specific nerves while leaving others functioning normally.

Nature Methods, 2012. DOI: 10.1038/nmeth.1897 (About DOIs)