Common Genetic Variant Dampens Pain

At Least One Quarter of People Estimated to Carry Pain-tolerant Haplotype

How we handle pain is often assumed to reveal something about our character. A person who suffers stoically or bounces back after an injury is seen as brave, while another person who constantly feels pain and remains bedridden after surgery might be branded as weak or complaining. But what if our ability to feel and tolerate pain were as programmed as our height or hair color? Our response to pain is undoubtedly more complex, but research is showing that the perception of pain varies among animals and people, and at least some of the differences are based on genetics.

Photo by Graham Ramsay

“There is a heritable component of the way we react to pain,” said Clifford Woolf (second from right), who, with lab members (from left) Michael Costigan, Joachim Scholz, and Alex Binshtok, uncovered a molecular pathway that helps determine pain sensitivity.

In a study published online Oct. 22 in Nature Medicine, Clifford Woolf and colleagues identify a biochemical pathway that helps control how animals respond to pain by altering levels of neurotransmitter production. Further, the researchers reveal a genetic variation in some humans that is associated with lower pain sensitivity and a faster recovery after surgery.

“It started off as a fishing expedition,” said Woolf, the Richard J. Kitz professor of anesthesia research at Massachusetts General Hospital. His team was conducting multiple microarray analyses on cells to identify all the genes that were switched on or off by pain responses in the peripheral nerves and spinal cord of rats. From a sea of 1,500 genes that surfaced, the team was able to narrow the candidates successively, first by limiting them to genes that were upregulated for months at a time and then focusing on those shared by three different pain models. Still faced with more than 100 genes, the team then looked for genes that were part of a complex or pathway, which might be more significant than a gene acting alone. With that, the researchers found their fish: three related genes that were highly active in injured nerve cells.

The Regulator
The genes were involved in synthesizing BH4, a cofactor needed to produce critical signals in neurons, such as nitric oxide, serotonin, dopamine, and norepinephrine. This molecule had been well studied, but not as a regulator of pain. Woolf said that BH4 is known to play a necessary role in the synthesis of these signals. But “what wasn’t appreciated is if you have more of the cofactor, you get more of the reaction,” he said. It was possible that too much BH4 might lead to neuropathic pain, which some people experience after nerve damage, injury, or medical conditions like arthritis and diabetes.

Models for pain sensitivity measure the threshold at which an animal withdraws its hindpaw when exposed to a stimulus like touch or cold. When the animals have a nerve injury elsewhere in the body, they become hypersensitive to these signals. “Sensory information in undamaged axons is interpreted as pain,” Woolf said. Woolf’s team found that BH4 and its related enzymes were upregulated in these animals and that injecting a drug that inhibits GTP cyclohydrolase, one of the enzymes involved in producing BH4, could return the rats to normal sensitivity. “It didn’t make them unreactive; it just removed the abnormal pain hypersensitivity,” Woolf said. Injecting BH4 into normal rats could also make them extra sensitive to pain.

The Less Sensitive Type
Meanwhile, Mitchell Max, a co-author on the paper and chief of clinical pain research at the National Institute of Dental and Craniofacial Research, was also looking for causes of pain hypersensitivity, but from a different angle. Max had learned that pain sensitivity was about 50 percent heritable in mice and rats. He wanted to explore the genetic basis of pain in humans and to bring some of the growing molecular knowledge about pain in animals to bear on human genetics. Max identified a large pain study in humans that offered data on patients’ responses to pain, collected blood samples from the patients, and began scanning their DNA for differences in the most likely pain genes. Unfortunately, “it was a total bust,” he said.

He talked with Woolf’s group, knowing that they had been performing a series of microarray studies. They suggested their top gene candidates, including those in the BH4 pathway. Using data from a group of 168 people who had undergone spinal-disk surgery as a treatment for sciatica, Max’s team discovered a genetic variation that seems to protect against undue pain: a haplotype of the gene encoding GTP cyclohydrolase (GCH1) that was associated with less pain a year after surgery. The variant is common—25 to 30 percent of people have at least one copy. In another cohort of 400 people who were tested for responses to experimental pain, those who carried two copies of the protective haplotype were significantly less sensitive to pain.

To determine how the genetic variation works, the team examined blood cells of patients from the first cohort and found that cells of patients with the protective haplotype produced less BH4 when they were stimulated with a drug that leads to the transcription of GCH1. Presumably, the genetic variation works in neurons in the same way. “The gene is fine, but it doesn’t respond in the same way to transcription factors,” Woolf said. A subtle change in GCH1 could have wide-ranging effects on the dynamics of neurotransmitter production, keeping a cell from responding too aggressively to stimuli.

Woolf said that certain people who tolerate unpleasant conditions, such as having their arm placed in a bath of ice water, often fare better after surgeries. “We now think it’s because those individuals really do feel less pain,” he said. Though most genetics has focused on mutations that cause disease, “here we’ve got a mutation that’s actually adaptive; it protects you. There are people out there who are not insensitive to pain, but just feel less pain than others.”

Max said that genetic studies can help translate basic research in pain into drug development: a protective phenotype offers evidence that this pathway is important in humans. Woolf is involved in a company, Solace Pharmaceuticals, that will be looking for ways to target this pathway chemically in humans. The researchers speculate that many other genetic variations underlie the pain response, and it will be interesting to see whether some of the behavioral and lifestyle differences among people can be explained by their differing abilities to feel pain.

—Courtney Humphries

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