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November 16, 2006

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Sensitivity to pain explained

Could be key to easing chronic pain

By William J. Cromie
Harvard News Office

Clifford Woolf and his colleagues have found the first human gene associated with pain. Variants of the gene make people more or less sensitive to pain. (Staff photo Rose Lincoln/Harvard News Office)

Stabbing back pain or the aches of arthritis send some people to bed in misery while the same distress seems easily tolerated by others. Why does pain hurt some people more than others? Scientists finally have an answer.

It involves a single molecule under control of a gene that acts like a dimmer switch. A "bright" or high setting excites sensory nerves to produce more of a chemical called BH4. For scientists, BH4 has one meaning, but for sufferers, it might as well mean "Big Hurt." Lower settings block BH4, protecting people from the wrench and bite of chronic pain.

The discovery offers tantalizing hints of "hurt markers" that forecast how people will react to pain. For example, the research results might quickly be adapted for surgery patients. Those with genetic dimmer switches set on "high" would be treated more aggressively with painkillers. Even more intriguing, further investigation may lead to new ways of preventing the onset or continuation of chronic pain.

"This is the first evidence of a genetic connection to the risk of developing chronic pain," notes Clifford Woolf, Richard J. Kitz Professor of Anaesthesia Research at Harvard Medical School. People who do not have a pain-protective variety of the gene, called GCH1, which controls production of BH4, feel the most pain. Those who inherit one copy from their parents, about 25-30 percent of us, receive enviable protection. Those who are born with two such gene forms, one each from their father and mother, are the luckiest. They comprise about 2-3 percent of the population.

"This gene variant appears to be a marker both for less pain sensitivity and a reduced risk for acute or short-term pain becoming chronic pain," Woolf points out. "Identifying those at greater risk of developing chronic pain in response to medical procedures, trauma, or diseases could lead to new strategies for prevention and to potential new treatments."

Woolf is part of an international team, led by researchers from Harvard Medical School and its affiliate Massachusetts General Hospital in Boston, who reported their findings in the November issue of Nature Medicine.

Picking the brains of rats

About 50 million adults in the United States suffer from chronic or persistent pain, according to an article on the subject in the journal Science. It accounts for more than 20 percent of doctor's visits and 10 percent of the trillions of dollars spent on health care.

Until recently, pain sensitivity was thought to be a product of upbringing and environment. Pampered people, sissies, and weaklings felt pangs that tough stoics did not. But in the past 15 years or so, evidence of pain genes has been showing up in laboratory animals. Experiments reveal that related groups of mice and rats have significant differences in how much distress they feel from nerve damage or from inflammatory conditions like arthritis. GCH1 is the first human gene variant ever associated with the intractable hurt caused by nerve damage.

To find it, Woolf and his team looked for those genes that switched on or off in lab rats with damaged nerves. That turned out to be a difficult, tedious task. They found 1,500 genes. After much labor, they narrowed the genes down to about 150, then three, then GCH1 which, when activated, produces the protein that make BH4.

When ready to turn their investigation to humans, the researchers looked at 168 patients who had participated in earlier studies done by Mitchell Max of the National Institute of Dental and Craniofacial Research. These people, who had undergone back surgery to relieve leg pain from a herniated disk, were asked about how much pain they felt a year after their operations. Sure enough, those with a variant of GCH1 that makes less BH4 complained less about their aches than those without it.

To see if that gene is linked with other types of pain, the researchers recruited 400 healthy people who volunteered for slightly painful pinches, sticks, and heat in lab experiments. Again, lucky ones with the less active form of GCH1 reported less discomfort. Those with two copies of this form were least sensitive.

"These results suggest that individuals who say they feel less pain are not just stoics but genuinely have inherited a gene variant that reduces their perception of pain," Woolf concludes. "This perception results not from personality or culture, but from real differences in the biology of the central nervous system."

New types of painkillers

Anyone can immediately think of good uses for a quick blood test that provides an estimate of how much a surgical procedure or a slipped disk is likely to hurt. Woolf thinks that the first application of his research will be pain kits for those undergoing surgery. For example, cancer treatments often damage nerves, producing pain that limits the therapy, a frustrating situation.

"It should be possible to mimic the action of GCHI with drugs," Woolf proposes. "Human genetics has showed us how the risk of pain is reduced naturally. Now we need drugs that convert unfortunate pain-sensitive people into fortunate pain-insensitive individuals. The right drugs might reduce both postsurgical pain and prevent the establishment of chronic pain," Woolf says.

Researchers would also like to determine how much relief this gene variant gives people with painful ailments like arthritis, diabetes, and chronic backaches. More investigation is needed into the precise workings of the pain dimmer switch before researchers can come up with good answers and, perhaps, more-effective drugs with fewer side effects.

Woolf also wonders about the effects of these gene variants on behavior. "Are pain-protected people drawn toward potentially painful activities, such as extreme sports and marathons, more strongly than others?" he asks.

To extend such musings even further, police and fire departments, or the armed forces, might consider recruits with the right gene as more desirable than those without that advantage. The Marines might look for men and women with a few good GCH1s.

Such speculation aside, Woolf calls this new research area "exciting," and says, "I am very optimistic that we will be able to mimic what nature does to ease pain."


Copyright 2006 by the President and Fellows of Harvard College