Scientists Discover Genetic Basis For Individual Variations In Pain Perception And A Common Chronic Pain Condition

An age-old question is why some people seem to be able to withstand high levels of discomfort while comparable pain causes others to cry for mercy. A related question is how some people can live through major physical and psychological stresses with no apparent consequences while others develop chronic pain conditions.

Now, University of North Carolina at Chapel Hill scientists, collaborating with National Institutes of Health, the University of Adelaide and Attagene Inc. researchers, say they have discovered a major part of the answers to both questions.

The key is genetics, the scientists say. Subtle variations in certain genes can make one person highly sensitive to pain and more susceptible to developing chronic pain disorders, while other variations can be protective.

"Our findings are extremely exciting and will interest the general public and the medical community," said Dr. William Maixner, professor at UNC’s Comprehensive Center for Inflammatory Disorders and director of the UNC School of Dentistry’s Neurosensory Disorders Unit.

In their five-year study to determine the relationship between pain sensitivity and development of chronic pain, he and colleagues found that humans have a tremendous range in pain sensitivity.

"Some people are very resistant to pain like they have taken a clinical dose of morphine," Maixner said. "More importantly, people who are less sensitive to painful stimuli are protected from developing a very common and debilitating pain condition called temporomandibular joint disorder (TMJD). These variations in pain sensitivity are stable over time, suggesting a genetic predisposition."

By concentrating on the genetics of COMT, an enzyme that controls levels of epinephrine and other chemicals and is released in response to stress, the scientists could explain significant variations in pain sensitivity.

The experiments were led in part by Dr. Luda Diatchenko, research associate professor at the inflammatory disorders center. They involved 202 healthy women, whose COMT gene variants, pain sensitivity and risk for TMJD were analyzed. Molecular biological, cell culture and animal behavior experiments were also conducted to demonstrate the relationship between COMT activity and pain sensitivity.

"We identified three genetic variants of COMT that are highly prevalent in the human population," Diatchenko said. "This is the first demonstration that a genetic variation influences both human pain perception and the risk for developing a chronic pain condition."

"By analyzing slight differences in the gene that produces the COMT enzyme, we can predict the risk of developing TMJD, which is both common and costly and impacts more than 10 percent of the U.S. population," said Dr. Gary D. Slade, formerly a UNC clinical epidemiologist now at the University of Adelaide.

The researchers believe their discoveries will apply to conditions such as fibromyalgia syndrome, irritable bowel syndrome and several other chronic sensory disorders that are also characterized by enhanced pain sensitivity and are frequently seen in patients with TMJD.

A report on the findings will appear in January in Vol. 14 of the journal Human Molecular Genetics.

"These results have broad ramifications for our understanding of pain physiology and genetics, for the development of genetic markers of pain conditions and for devising new and better strategies for treating pain," Maixner said.

He, Diatchenko and their team are now identifying additional genes that contribute to both pain sensitivity and TMJD, he said. They also have begun investigating new drug therapies for treating TMJD and related conditions.

Other UNC authors of the report are Drs. Andrea G. Nackley, a postdoctoral fellow in the neurosenstory disorders unit; Asgeir Sigurdsson, former associate professor of endodontics; and Konakporn Bhalang, a former graduate student in oral biology now with Chulalongkorn University in Bangkok, Thailand.

Others are Drs. Inna Belfer, David Goldman, Ke Xu, Svetlana A. Shabalina and Mitchell B. Mask of the National Institutes of Health; Dr. Dmitry Shagin of the Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry in Moscow, Russia; and Sergei S. Makarov of Attagene Inc. in Research Triangle Park, N.C.

Support for the research came numerous sources including the National Institutes of Health and Attagene Inc. of Research Triangle Park, N.C.

"This is an outstanding example of translational, multidisciplinary research," Maixner said. "It involved a host of collaborative players -- from clinicians, physiologists, epidemiologists, molecular biologists and geneticists to the UNC School of Dentistry and federal granting agencies such as the NIH and Attagene Inc. representing private industry."