Chronic-pain treatment without side effects

A drug has been found that treats chronic pain in mice, without the usual painkiller side effects of sedation, addiction or developing tolerance.

Whether the compound has the same effect in people remains to be seen, but researchers are approaching the drug’s target with “cautious optimism”.

The compound comes from a well-known class of drugs, the benzodiazepines, that are widely used for sedation or to treat anxiety. Benzodiazepines act on brain pathways involved with pain perception, but have not been very effective at relieving pain. A team led by Hanns Ulrich Zeilhofer of the University of Zurich in Switzerland wanted to know why.

They first tested diazepam — commonly known as valium — by injecting it into the spines of mice. The spine is one of the body’s direct pain highways, so blocking pain signals here might help avoid side effects that turn up when a drug hits the brain. In this system the researchers found that diazepam could indeed relieve pain — mice that either endured a painful injection or had a nerve squeezed to simulate chronic pain were less bothered if they received the spinal injections.
Receptive strategy

Researchers know that valium acts on a receptor called γ-aminobutyric acid, or GABA, in the spine, and that GABA has different parts or subunits that might be responsible for the different effects of the drug. To investigate, the team looked at four types of mutant mouse, each of which had a different subunit of this GABA receptor rendered inactive, to see what valium would do.

They found that two of the subunits, α2 and α3, had to be present for the drug to relieve pain. Thankfully it is a different subunit, α1, that causes sleepiness when the drugs hit the brain. The researchers report their results in Nature 1.

“What we have shown is which receptors need to be targeted,” says Zeilhofer. Being able to zoom in on the target like this is what’s most exciting about this work, says Clifford Woolf, an anaesthesiologist at Massachusetts General Hospital in Charlestown.