The difference between a child who laughs off skinned knees and one who cries at the smallest pinch could be in their DNA. Subtle changes to a certain gene seem to determine how sensitive people are to pain, according to new research.

In the past 5 years, researchers have discovered that three rare but serious pain disorders are caused by mutations in a gene called SCN9A. In nerve cells that relay painful sensations in the body's tissues to the central nervous system, SCN9A encodes instructions for sodium channels that help the cells fire. In two of the disorders, people carry faulty versions of the gene and suffer crippling pain because their sodium channels open too easily or can't close. In the third disorder, which leaves patients unable to feel pain at all, SCN9A produces a protein that can't function.

"We wondered if more common, apparently harmless [changes] in the gene might give rise to an altered degree of pain threshold," says Geoffrey Woods, a medical geneticist at Cambridge University in the U.K., who discovered the genetic reason for this third disorder. So he and his colleagues examined differences in SCN9A in 578 patients with osteoarthritis. Controlling for the severity of the condition, they checked whether the patients' pain level was related to any one of 27 subtle genetic variations, known as single-nucleotide polymorphisms (SNPs), in SCN9A.

One SNP, found in 10% of the subjects, caused the greatest increase in reported pain between those who had it and those who didn't. The team then looked for the SNP and compared it to reported pain in four other groups: 195 Finnish people with sciatica; 100 Danish amputees, some of whom experienced phantom limb pain, or pain in the limbs they had lost; 179 people who had had a lumbar disk removed to treat lower back pain; and 200 people with pancreatitis. Sciatica patients and amputees who reported more pain were more likely to have the SNP. The researchers also saw a positive trend, though not a statistically significant one, among the lower-back-pain patients and pancreatitis patients. But when the groups were combined, the statistical link between having the rare SNP and feeling more pain was impressively strong. When the team applied heat stimuli to 186 healthy women, they found that those with the rare version were more likely to have lower pain thresholds. It was as if the normal subjects had taken an ibuprofen, but the subjects with the rare SNP hadn't, Woods says. His team reports the results online today in the Proceedings of the National Academy of Sciences.

Woods's group also sought to determine how the SNP was causing more pain. When they placed the altered SCN9A gene in kidney cells, which serve as blank slates because they don't have this sodium channel, they found that the cells grew sodium channels that were "slightly less efficient" at squeezing shut after they had let sodium in and triggered the neuron, Woods says.

Woods warns that this effect is so subtle that it might not be directly due to the SNP. But the results do seem to show that sensitivity to pain is hard-wired. "Some people are stoic and some aren't. ...Maybe there's a plausible biological reason for that difference," Woods says.

In the groups Woods studied, between 15% and 18% of patients had one copy of this variant, while 2% to 3% had two copies of the variant, making them even more sensitive to pain. Meanwhile, about 20% of adults develop chronic pain, a statistic that's been "very difficult to link with the severity of injury and the severity of ongoing damage," says MacDonald Christie, a neuroscientist at the University of Sydney in Australia. This genetic variation "could go part of the way to explaining why some people have much more serious chronic pain than others."