In your old comic books, it’s simple. A few punches. Sharp, fleeting pain. Then it’s over.

That type of pain happens in real life too. But more often, the pain that puts us in the examining room isn’t colorful, and it isn’t quick — it lasts for weeks, months, even years. LaDonna Lindstedt, for instance, visited an ear, nose, and throat (ENT) specialist because of earaches and trouble hearing as well as daily “droning, constant” headaches. Occasionally she’d have a headache so bad she couldn’t open her eyes.

Before the headaches started, Lindstedt had experienced episodes of jaw pain and tension. She’d know it was coming on because “the first bite of anything I ate was excruciating,” she says. “It actually felt like an electric shock running through my jaw and my head.” Over a week, the pain and tightness would get so severe that she could open her mouth only wide enough to drink through a straw.

The ENT specialist diagnosed Lindstedt with Temporomandibular joint disorder (TMD), a chronic pain condition that affects 5 to 15 percent of the population. Like many chronic pain disorders, TMD has no apparent cause. The patient hurts all the time, but often x-rays and other tests don’t show tissue damage or inflammation.

In the three hundreds B.C., Aristotle suggested that pain was not a physical sense but an emotion. Today, most scientists would agree that pain is physical — the stuff of nerve fibers and receptors and chemicals. But for some chronic pain disorders, we wonder. Often these types of pain get labeled as possibly psychogenic — psychological in origin with no biological cause.

A study from Carolina shows that the pain is real. But the source won’t show up on an x-ray; it is in the genes, and in the firing of brain cells. This research is the first study to link a genetic variation with a chronic pain disorder.

This discovery took seven years of work from a team of thirteen scientists. One of those researchers is William Maixner, a pharmacologist, neuroscientist, and dentist. Maixner is a genial man with blue eyes, ruddy skin, and wavy hair turned mostly gray. In Carolina’s Oral and Maxillofacial Pain Clinic, he sees patients with TMD, including LaDonna Lindstedt. Her treatment includes twice-a-week physical therapy, nightly muscle relaxants, and a mouth guard to wear when she feels her jaws are beginning to clench. Such treatments help, but scientists still don’t know exactly what causes pain disorders such as TMD. Maixner says, “Patients will come to me and say, ‘I don’t see any reason why I should be having this pain. Do I have a brain tumor? Am I crazy?’”

Scientists know that, in general, people who suffer from chronic pain disorders are more sensitive to pain and often struggle with mild depression and anxiety. But which comes first: the pain disorder, or these other symptoms? And what makes some people, especially women, more likely to get chronic pain disorders?

Researchers have suspected that the answers may lie partly in genetics; animal studies have suggested that as much as 50 percent of pain sensitivity is inherited. Enter Luda Diatchenko, a geneticist who earned her M.D. and Ph.D. degrees in Moscow. Diatchenko is petite, with dark, bobbed hair. She came to Carolina in 2000 after years of developing technology for gene expression and regulation at CLONTECH, a California biotech company. “I look at things from the level of the molecule,” she says, in her lilting voice with a Russian accent. “What changes in the molecule lead to the consequences that you see?” Diatchenko is excited about trying to trace some big consequences — pain and perception — all the way back to a tiny part of a gene.

Diatchenko’s research has led her to a gene that codes for an enzyme called COMT. The COMT enzyme breaks down the stress hormone epinephrine. Most people produce plenty of COMT, so they get rid of epinephrine — and stress — quickly. But Diatchenko has found that there are two variations of the gene that cause the body to produce lower levels of COMT.

“So if you have low levels of COMT, you’re not getting rid of epinephrine, and you’re potentiating the stress response,” says Maixner, sitting at a conference-room table with Diatchenko.

Diatchenko, listening closely, interjects: “So you have epinephrine circulating in your body again and again, endlessly.”

This gets Maixner going. “If epinephrine is there all the time, you have anxiety, you have increased pain sensitivity,” he says.

To explore the role of COMT in pain sensitivity, the team recruited 202 healthy women with no history of TMD. The researchers studied only women because they’re more likely to develop TMD and other chronic pain conditions. Part of that has to do with COMT, Diatchenko says. In general, the COMT enzyme’s activity is lower in females, partly because estrogen inhibits its expression.

“Females are more pain sensitive,” Maixner says. “Women are also more sensitive to almost all other senses — touch, temperature, vision, olfaction.”

Diatchenko jumps in. “I don’t know if Doctor Maixner agrees with me — I think it’s a philosophical question — but you can think of being more pain sensitive as having higher cognition,” she says.

As being more aware? “Aware, yes,” Maixner says.

“Aware of the stimulus,” Diatchenko says. “So is it good or not to be high-cognition? It depends, right?”

The two start speculating that there might be a reason that women are more pain sensitive; maybe they evolved that way because they had to be alert to dangers and protect their young. But for men, who needed to hunt and sometimes get roughed up out there, it might have been an advantage to not be quite so attuned.

It’s an interesting idea. But Maixner brings the conversation back to the original topic — that women’s lower levels of the COMT enzyme mean higher levels of epinephrine and possibly more sensitivity to pain. Then he looks at Diatchenko.

“I think it’s still an open question about the issue of cognition,” he says. “Ahem!”

“Yes,” Diatchenko answers, “women have more cognition.” They both laugh.

The women participating in the study donated blood samples for genetic testing. They also agreed to be tested for their pain threshold and tolerance, using three different methods. Maixner and Diatchenko have taken these sensitivity tests themselves many times, both to tweak the methods and to feel what the subjects would be feeling.

In one procedure, an instrument called an algometer was used to apply a measured amount of pressure to various areas — the jaw muscle, the wrist. In a second test, a thermal stimuli was applied to the face, arm, and foot. The heat never went above 53 degrees Celsius (about 127 degrees Fahrenheit, well below the temperature that would cause a burn). Participants were also tested using ischemic pain — pain caused by obstruction of blood flow to a muscle. That was accomplished with a device similar to a blood pressure cuff.

In each of these tests, the patient signaled when they first found the procedure to be painful. The procedure was stopped. That amount of force or heat was recorded as the patients’ pain threshold. Then, on a second test, the participants were asked to endure the pain until they found it to be at the limit of their tolerance. “The patient always had complete control,” Maixner says. Diatchenko says that most subjects don’t consciously consider their responses; they are instantaneous. When Diatchenko, for instance, first touches the thermal electrode, she snatches her hand away “as if it were a hot stove,” she says. But others in the lab, testing it on their hands, will say, “Is this thermode even working?” Our pain sensitivity is “beyond us,” Diatchenko says. It is inherent.

The test results support that idea. The sum of all those measures gave each woman a score that showed, compared to others, how sensitive she was to pain. Each woman’s pain profile stayed relatively constant over the three-year study. And the scores followed a bell curve; the largest number of women fell somewhere in the middle, with only a few testing as very pain sensitive, and a few others as very pain tolerant. “This is what you would expect of a trait that has a least some component that is genetically determined,” Maixner says. “The distribution of pain sensitivity in the population began to appear to us as if it had more trait-like characteristics, almost like height or weight.”

After all the testing, the researchers tracked the women for three years. The subjects received a physical exam once a year and filled out online health questionnaires four times a year.

The team found that the women who had the tiny variations in the COMT gene were indeed more sensitive to pain. And they were also more likely to develop TMD.

Many researchers would have stopped there. But not this team. The human study had shown an association, a link, between the genetic variations and sensitivity to pain. But it did not show that the genetic variations caused the heightened sensitivity. So the scientists conducted two additional sets of studies. Postdoctoral fellow Andrea Nackley oversaw these experiments. Nackley, a neuroscientist with a background in animal behavior, is dark-eyed and enthusiastic. She wanted in on this project partly so she could learn hands-on genetics.

In test tubes, Nackley measured by-products of epinephrine metabolism in cells to show that the genetic variations in COMT that were associated with higher pain sensitivity did indeed result in reduced breakdown of epinephrine. She also backed up the team’s findings with an animal model — rats. Nackley administered two different drugs that inhibit the COMT enzyme. The drugs caused larger-than-normal amounts of epinephrine to circulate in the rats’ bodies, mimicking what the researchers think is happening with people who have variations in the COMT gene. If those variations truly cause sensitivity to pain, then the rats that received these drugs should be more pain-sensitive as well.

They were. “After we gave them the COMT inhibitor, their pain threshold was lower,” Nackley says. The testing procedures were similar to those used with the women. Nackley applied mild mechanical and thermal stimuli and measured the rats’ “paw withdrawal” rates. By the way, did these rats act differently than other rats? “Actually, yes,” Nackley says. “Their hair stands up a little bit. They defecate more. They do seem a little more stressed out in general.”

The researchers published the results of all the studies together, in the January 1, 2005, issue of the journal Human Molecular Genetics. The study has suggested new ways to treat chronic pain. Right now Maixner and Diatchenko are conducting a pilot clinical study using the drug propanolol to treat patients with TMD and another chronic pain disorder, fibromyalgia. The drug, which has been used in the past to treat hypertension and anxiety, blocks some of the body’s receptors for epinephrine.

Maixner believes that the research also demonstrates that people who suffer from chronic pain are not imagining it. “My view is that there’s a true neurological basis to these conditions,” he says. “I do not believe in psychogenic pain. I think the whole field now has moved away from this notion that there’s a separation between mind and body.”

For instance, many of our brain cells, including those involved in perceiving pain, are kept at rest by an active “inhibitory system.” This chemical system regulates your sleep-wake cycles and your levels of alertness, and it “allows you to move around in your environment without experiencing pain and discomfort,” Maixner says.

But this system may not work as well in some people. In patients with fibromyalgia, for instance, brain scans have shown increased activity in certain areas of the brain. “These regions become more excited in response to stimuli compared to others’ brains,” Maixner says. In other words, in some people, it doesn’t take much to get certain neurons firing. That genetic characteristic, when combined with an environmental trigger such as stress or physical trauma, may result in a chronic pain disorder.

Maixner believes that even if patients with chronic pain disorders don’t have damaged muscles or inflamed tissue, their pain does have a physical source. “There is pathology, but it’s within the central nervous system,” he says. This study supports that idea. For people with chronic pain disorders, the pain is in their genes, even in their brains. But it’s not all in their heads.end of story

Maixner is director of the School of Dentistry’s Neurosensory Disorders Unit. Diatchenko is research associate professor at the School of Dentistry’s Comprehensive Center for Inflammatory Disorders. Other members of the team are Carolina researchers Andrea Nackley and Asgeir Sigrudsson; Gary Slade of the University of Adelaide, Australia; Konakporn Bhalang of Thailand’s Chulalongkorn University; Inna Belfer, David Goldman, Mitchell Max, Svetlana A. Shabalina, and Ke Xu of the National Institutes of Health; Dmitry Shagin of Shemyakin and Ovchinnokov Institute of Bioorganic Chemistry in Russia; and Sergei Makarov of Attagene.