Chronic pain is remarkably common after major surgery, occurring after 15 percent of hernial repairs and up to 50 percent of mastectomies, for example. Various biological factors can change the sensitivity of pain receptors or how the nervous system processes their input, but the biological causes of chronic hypersensitivity to pain have remained mysterious. Looking for genes that might play a role, pain researcher Clifford Woolf of Harvard Medical School and his colleagues scanned for gene activity in rats given sciatic nerve injuries. They found a conspicuous uptick in the activity of several genes all involved in producing tetrahydrobiopterin (BH4), a chemical assistant to enzymes that manufacture nitric oxide and several neurotransmitters.
One of the more active genes encoded an enzyme called GTP cyclohydrolase (GCH1). Tellingly, when the researchers injected mice with an inhibitor of GCH1, the animals went from exhibiting signs of chronic pain to displaying normal pain responses, whereas injections of BH4 made the mice much more sensitive to pain, according to a paper published online October 22 in Nature Medicine.
The gch1 gene turns up in human pain, too. In a study of surgical disk removal for back pain, those with one copy of a gch1 variant--30 percent of the total--reported less frequent pain after surgery, the group found. Three percent of those studied had two copies of the variant and were at even lower risk for chronic pain. Similarly, in studies of temporary pain, people were less sensitive to pinches, heat and pressure if they possessed one or two copies of the gch1 variant. The protective variant becomes more active when chemically stimulated, suggesting that it kicks in after nerve damage and inflammation, and seems to work by influencing nitric oxide synthesis, the researchers report. "We really think we've uncovered a completely novel pathway with a novel regulator of pain," says Woolf, who founded a biotech to find inhibitors of the GCH1 enzyme. About 30 percent of people overall have the variant gene, he notes.
"The authors have done an elegant piece of work," says pain researcher Michael Salter of the University of Toronto. Linking the GCH1 enzyme to pain "is unprecedented and represents a marked shift in our understanding," he says. Applying the finding will require a lot of work, he cautions, but he adds that "this provides the basis for exploring entirely new types of drug therapies for pain in humans" and may eventually make it possible to tailor pain treatment to the individual.