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Study targets chronic misery

In a discovery that could eventually help improve the lives of chronic pain sufferers, California researchers have found a way to reset the pain "thermostat" in rats' brains.

Using gene therapy, they boosted the amount of a key neurotransmitter in a specific brain region, significantly raising the rats' pain threshold.

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To do this, the researchers injected the rats' brains with a gene that produces a key brain neurotransmitter called gamma aminobutyric acid (GABA). This protein acts as an inhibitor, generally dampening all kinds of neural activity. To limit the neurotransmitter's effect, the scientists injected the GABA-producing gene into one small cortical region, the rostal agranular insular cortex (RAIC). They had long suspected that the region plays a role in pain perception.

Once their RAICs were inundated, the rats reacted much less strongly to painful stimuli - a warm probe applied to their paw for several seconds. Researchers concluded that the increased GABA had dulled the animals' pain sensitivity.

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Published in last week's Nature, the study is the first work to positively establish GABA as a crucial pain-modulating neurotransmitter and also the first to nail down the RAIC as a vital pain perception center.

The discovery underscores the complexity of pain perception, said Luc Jasmin, a University of California, San Francisco neuroscientist who led the study. "Pain is not a crude sensation. It's a higher cognitive experience," he said.

Other experts called the study an important step in pain research. "This is huge - even in the rudimentary mammalian brain, the forebrain can modulate the signals that cause pain behavior," said neuroscientist Bud Craig, who studies pain at the Barrow Neurological Institute in Phoenix.

Although the technique has not been tested in humans, researchers say it could one day help some of the 50 million Americans with chronic pain.

"We could use this for a number of intractable pain conditions, including cancer pain and chronic pain," Jasmin said.

Over that past 10 years, researchers have increasingly realized the crucial role that the cortex - the most advanced part of the brain - plays in pain sensation. In the past, scientists thought that the cortex simply registered signals sent by peripheral nerves. But recent work has revealed that the cortex decides how much pain a given stimulus is causing.

"We always thought the cortex was the end of the road," said University of Minnesota pain researcher George Wilcox. "But ... it's a two-way road."

The cortex plays an especially large role in chronic pain. As the pain continues over months and years, the brain often lowers its pain threshold.

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"Most pain starts in the periphery," says Jasmin. "But if it persists for too long, for some reason the central nervous system resets itself so that the person is always perceiving pain, even when the real cause goes away. If you want to treat chronic pain, you have to go where it is, which is in the cortex."

Because it affects cortical pain perception, GABA gene therapy might help most with chronic pain - especially cancer pain, which is often not only severe but diffuse. "By treating the cortex, you affect the whole body," said Jasmin, a neurosurgeon who also treats pain patients.

Doctors usually soothe acute cancer pain with large doses of morphine and other opiates. While these drugs work well, they also have unpleasant side effects, including drowsiness and appetite loss. Most patients, especially those with a short time to live, would prefer a treatment that allows them to be alert and hungry. The gene therapy would probably not create those unwanted side effects, Jasmin said, because it works through a different neural pathway than do opiates.

The gene therapy technique would be a minor procedure, Jasmin said - an outpatient surgery, using a needle to inject the GABA-producing gene.

Within three to five years, Jasmin said, he hopes to begin FDA-approved human clinical trials of the treatment.


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