August 1, 2001

STUDY GIVES GLIMPSE OF HUMAN BRAIN'S NATURAL PAINKILLER SYSTEM IN ACTION

A unique study that looked at chemical activity in the brains of human volunteers while they experienced sustained pain and reported how they felt is providing new insights into the importance of the body's natural painkiller system--and the reasons why each of us experiences pain differently.

The results confirm long-suspected connections between pain-dampening changes in brain chemistry and the senses and emotions experienced by people in pain. The findings may help researchers better understand prolonged pain and find more effective ways to relieve it.

Results from the brain imaging study were published in the July 13 issue of Science by NIDCR-supported researchers from the University of Michigan Health System and School of Dentistry. It is the first study to combine sustained, induced pain with simultaneous brain scan monitoring of a key neurochemical system and the self-reported pain ratings of human participants.

The research cements the critical role of the mu opioid system, in which naturally produced chemicals called endogenous opioids, or endorphins, match up with receptors on the surface of brain cells and reduce or block the spread of pain messages from the body through the brain. The mu opioid receptor in particular has been found to be a major target for both the body's own painkillers, as well as for drugs such as heroin, morphine, methadone, synthetic pain medications and anesthetics, which also numb pain.

The study found that the onset and slow release of jaw muscle pain over 20 minutes caused a surge in the release of the chemicals. It also found that the flood of those chemicals coincided with a reduction in the amount of pain and pain-related emotions the volunteers said they felt. Specific brain regions, especially those already known to play a role in affective, or emotional, responses, and those known to help process signals from the body's sensory systems, had the biggest increase in the level of opioids when pain was introduced. The research also revealed major variation among volunteers in the baseline and pain-induced levels of opioids.

"This result gives us new appreciation for the power of our brain's own anti-pain system, and shows how brain chemistry regulates sensory and emotional experiences," said lead author Jon-Kar Zubieta, M.D., Ph.D., assistant professor psychiatry and radiology at the University of Michigan Medical School and assistant research scientist in the Mental Health Research Institute.

Zubieta and his colleagues used positron emission tomography, or PET, a technique that allowed them to have a unique window into the chemical activity of the volunteers' brains. To narrow their view to the mu opioid receptor system, they attached short-lived radioactive carbon atoms to minute quantities of a molecule known to bind only to mu opioid receptors. This game them a tracer whose radioactive decay signals, followed over time, allowed them to measure the release of endogenous opioids and the activation of the mu opioid receptors.

With their view onto the brain's pain mechanism ready, the researchers looked at prolonged jaw pain, mimicking the chronic condition of temporomandibular joint disorder (TMJ). To stimulate TMJ's symptoms, they devised a way to inject high-concentration salt water directly into each volunteer's jaw muscle, which caused a painful sensation that continued only as long as water was injected. A placebo solution that does not cause pain also was used for comparison. Rather than limiting the pain to a few seconds as in prior studies examining pain, they administered the solutions for 20 minutes. This allowed them to achieve the brain conditions and emotions much more closely related to those seen in chronic pain conditions like TMJ.

While the volunteers were scanned during the two injections, they were asked to rate how much pain they were feeling, giving a rating via a computerized system every 15 seconds. The same computer system then controlled the intensity of the pain stimulus so that each volunteer's own rating would be about the same throughout the 20 minutes. This allowed the researchers to compare the response of the brain's anti-pain system across individual subjects. Afterward, the volunteers completed a questionnaire about how the experience made them feel.

The results, said Zubieta, showed a brain chemistry response that was strongest in the brain regions where sensation and emotion are rooted--a response tied directly to the ratings of the pain experience that the volunteers gave. "We saw an intense activation of the mu opioid system in areas such as the amygdala, the thalamus, the hypothalamus, the frontal cortex, and the nucleus accumbens, as much as a 12 percent change over baseline conditions," he added. "And the higher the level of activation, the lower the scores the volunteers gave for pain-related sensations and emotions like feelings of the unpleasantness of pain."

The results also showed wide individual variations in the intensity of the brain anti-pain response, which correlated with the individual's sensory and affective responses to the pain experience--even though the computer system had ensured that all participants had experienced similar pain intensity. The activation of the anti-pain response was dramatic in some volunteers when the placebo and pain-inducing conditions were compared, while in others the response was much less pronounced. And those who had the biggest change tended to rate the experience of pain, both in its sensory and emotional aspects, the lowest.

"This may help explain why some people are more sensitive or less sensitive than others when it comes to painful sensations," Zubieta explained. "We show that people vary both in the number of receptors that they have for these anti-pain brain chemicals, and in their ability to release the anti-pain chemicals themselves. Both of these factors appear to determine the emotional and sensory aspects of a painful experience. Such variability in the pain response system may help explain why some people react to pain and pain medications differently. It may also be quite relevant to why some people, but not others, develop chronic pain conditions."

In addition to Dr. Zubieta, the research team included Yolanda Smith of the Department of Obstetrics and Gynecology; Joshua Bueller and Yanjun Xu of the Department of Psychiatry and Mental Health Research Institute; Michael Kilbourn, Douglas Jewett, Charles Meyer, and Robert Koeppe from the Department of Radiology; and Christian Stohler from the School of Dentistry.