Published online 16 January 2008 | Nature | doi:10.1038/news.2008.443

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Chronic-pain treatment without side effects

A common class of drug could be targeted to give better pain relief.

Ouch: relief for chronic pain would be great if it worked without making patients sleepy.Punchstock

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 Nature1.

"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.

Drug development

If giving drugs via the spine was practical in humans, the team could just use benzodiazepines in this way to relieve pain without side effects. But this requires a catheter and is not suitable for most patients.

So knowing which parts of GABA to aim for, the team tested the effects of a benzodiazepine known not to act on the α1 sleep-inducing bit of the GABA receptor: a compound memorably named L-838,417. They gave the compound orally to rats and it worked to relieve pain without sedating them like other painkillers. Moreover, it didn’t lose its effect when treatment continued for a few days. This issue of tolerance is a problem for drugs such as morphine.

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Additionally they imaged the rats’ brains with functional magnetic resonance imaging to see what effect L-838,417 was having on pain-processing areas. As expected, the drug reduced activity in brain areas related to pain, as well as in areas known to be involved in the emotional distress that comes with hurt.

The next step is to find drugs that will act the same way in humans. Some α1-sparing benzodiazapines are already being developed for the treatment of anxiety without sleepy side effects. But the α2 and α3 might not be the same in people as in rodents.

Woolf is adopting an attitude of "cautious optimism" towards these results. "It’s always a long way between pre-clinical studies and proof-of-concept in man," he says. 

  • References

    1. Knabl, J. et al. Nature 451, 330-334 (2007). | Article |
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