One form of a common genetic variant may ratchet up pain sensitivity in people who have it, researchers report online March 8 in the Proceedings of the National Academy of Sciences.
The discovery could lead to more powerful pain treatments that lack the debilitating side effects of current drugs. “We could fill our clinics many times over with people with chronic pain that we can’t help with our current medications,” says neurologist and neuroscientist Stephen Waxman of Yale University School of Medicine and the Veterans Affairs Connecticut Hospital in West Haven.
In the new study, researchers led by clinical geneticist Geoffrey Woods of the Cambridge Institute for Medical Research in the United Kingdom examined the DNA of 578 people with the painful condition osteoarthritis. Woods and his colleagues searched for genetic variations that might be linked to how much pain a patient reported feeling — a subjective measure, Woods says, but currently the best researchers can do.
The team found that people who reported higher levels of pain were more likely to carry a particular DNA base, an A instead of a G, at a certain location in the gene SCN9A. The A version is found in an estimated 10 to 30 percent of people, Woods says, though its presence varies in populations of different ancestries.
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This gene version may set the pain threshold, he says. “You’re more sensitive to pain.”
The same trend — higher pain levels reported by people who carried the A — held true in cohorts of people with other painful conditions including sciatica, phantom limb syndrome and lumbar discectomy. The A variant wasn’t strongly associated with higher pain scores in patients with chronic pancreatitis, however. Woods says that might change as more people are added to the study.
The researchers also looked for the gene variant in 186 healthy women who had been assessed based on their responses to a number of painful stimuli. The women with the highest responses were more likely to have the A variant instead of the G.
The genetic variation affects the structure of a protein that sits on the outside of nerve cells and allows sodium to enter upon painful stimuli. The sodium influx then spurs the nerve cell to send a pain message to the brain.
This channel protein is a promising target for extremely specific and effective pain drugs, Waxman says: “Given that this channel has been indicted, it would be nice if we could develop therapeutic handles that turn it off or down.”
Researchers already knew that people with mutations in SCN9A can have extreme pain syndromes. Genetic changes that render the protein completely inactive can leave a person impervious to pain, although otherwise healthy. Other mutations can lead to conditions such as “man on fire” syndrome, in which people experience relentless, searing pain.
Although these syndromes are extreme cases, they strongly implicate SCN9A as important for pain thresholds, Waxman says. The new study is “an important paper that advances our understanding of pain.”
In additional laboratory studies, the researchers found that nerve cells carrying the A variant of the gene took longer to close their sodium gates, allowing a stronger pain signal to be sent to the brain. Nerve cells carrying the more common G version of the gene snapped shut faster, stopping the pain signal sooner.