Why do high levels of the COMT enzyme, such as those found in subjects with the LPS haplotype, dampen sensitivity to pain? In experiments with rats, Diatchenko and Andrea Nackley homed in on adrenergic receptors, proteins in neurons that bind to molecules such as adrenaline and may trigger a stress response. Previous studies had linked these receptors to pain, especially that caused by rheumatoid arthritis. When the researchers blocked beta 2- and beta 3-adrenergic receptors, COMT no longer affected pain sensitivity, suggesting a specific target for pain treatment. Zubieta found another target in 2003 when he determined that the mu-opioid pathway (the brain’s internal reward system) is involved with COMT’s effects, though it’s not yet clear exactly how the two pathways relate.

Other studies in this young field suggest that COMT may not play a role in all types of pain. For example, a 2004 National Institute of Dental and Craniofacial Research (NIDCR) study of 500 people found no link between met158 and sensitivity to heat and cold, and the following year Spanish researchers could find no connection between met158 and sensitivity to neuropathic pain. And recently, a group from Norway determined that met158 was not associated with chronic musculoskeletal complaints or migraines. These divergent results might be explained by differences in the duration of the pain administered, the circumstances (whether the pain was inflicted in a lab or occurred after an operation) and the types of stimuli. Larger studies, Zubieta says, should help explain these discrepancies.

Researchers have known about COMT for a few years, but the pain gene Woolf and his colleagues reported in November 2006 came as a surprise. Because Woolf is interested in neuropathic pain, he injured the sciatic nerve of a rat, then looked for genes activated in response. He found 1,500—far too many to study—so he examined only those that stayed turned on six weeks after the injury (and thus seemed to be involved in chronic pain). He further narrowed the study by limiting it to genes linked in some way, assuming that there were major pathways with multiple genes that perpetuated chronic pain. There were three, one of which was GTP cyclohydrolase (GCH1). GCH1 raises levels of tetrahydrobiopterin (BH4), a molecule that helps enzymes make important neurotransmitters such as serotonin and dopamine, and Woolf found that the gene also strongly modulates pain sensitivity. “If we blocked synthesis of BH4, you got pain reduction, and if we added BH4, it produced pain,” Woolf says. BH4 turned out to be implicated in inflammatory pain as well.

Turning back to humans, Woolf enlisted neurologist Mitchell Max at the NIDCR. Max screened the blood of 168 back-surgery patients for the three pain genes Woolf had investigated in rats to see whether haplotypes of those genes were associated with more or less chronic pain following surgery. He found that one GCH1 haplotype was highly associated with lower levels of persistent leg pain. Then Max and Roger Fillingim at the University of Florida tested a set of healthy people for the pain-protective GCH1 haplotype and discovered that those with two copies (one from each parent) were less than normally sensitive to thermal, mechanical and deep-muscle pain.

Armed with new knowledge about the workings of COMT and GCH1, researchers have begun to develop drugs to treat pain. Woolf has filed for a patent on his work on GCH1 and is working with a Boston startup called Solace Pharmaceuticals (Woolf is a stakeholder in the company) to find ways to manipulate levels of BH4 in the body to reduce neuropathic and perhaps inflammatory pain. But he’ll have to find a drug that modulates BH4 without destroying its beneficial effects, including regulating dopamine and serotonin, which affect mood and movement, among other things.

Another potential use of the work on pain genes would be to screen patients about to go under the knife for genes that may predispose them to greater neuropathic pain. That would alert anesthesiologists and surgeons to take extra care to avoid nerves and provide adequate medication. In that way, Woolf thinks, neuropathic pain might someday be avoided completely. “We’ll identify who’s at risk and treat them very aggressively when they have surgery or get an attack of shingles,” he says.

Meanwhile, Diatchenko’s discovery that COMT works via the beta 2- and beta 3-adrenergic receptors has led her to consider drugs already on the market that block beta adrenergic receptors. Some have been used successfully to treat migraines and fibromyalgia, but have many side effects, such as depression and asthma. Medications that target just the beta 2 and beta 3 receptors might avoid some of those problems.

Much more research is needed before better pain drugs come on the market or before everyone can be tested for genetic sensitivity to pain. Diatchenko is doing some of that work, sharing a $19 million National Institutes of Health grant with researchers at four sites to follow 3,200 people for seven years to see which ones develop TMJD. The researchers will then assess the subjects’ genes and other risk factors to try to determine why this condition struck them. Such work, Woolf thinks, will ultimately lead to the creation of different drugs for people who have different types of pain, and that should have a profound effect on the lives of the millions like Terrie Cowley, who now, all too often, are told their trouble is all in their heads. “Instead of blaming people for their pain, we’ll be able to say, ‘You do feel more pain,’” notes Woolf. “And we’ll be able to do something about it.”

  Dossier

1. “COMT val158met Genotype Affects mu-Opioid Neurotransmitter Responses to a Pain Stressor,” by Jon-Kar Zubieta et al., Science, Feb. 21, 2003. In one of the first papers linking human pain to a particular gene, Zubieta details his elegant experiment and uncovers a possible target for future pain medications.

2. “Feeling Pain? Who’s Your Daddy...,” by Gavril W. Pasternak and Charles E. Inturrisi, Nature Medicine, November 2006. A commentary on Clifford Woolf’s pivotal finding that pain is partly in your genes, this paper provides an excellent description of neuropathic pain and how Woolf’s discovery may be a major step toward preventing such pain.

3. “One Size Does Not Fit All,” by Ruth Landau, Anesthesiology, August 2006. An editorial that discusses the genetic reasons why certain painkillers don’t work very well in some of us.