Pain, Itself, Elicits Pain Relief,
And Does So Through "Reward" Pathway

Study Gives First Glimpse Of Human Brain's Natural Painkiller System In Action

ANN ARBOR, MI - A unique experiment that studied 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.

The double-blind, placebo-controlled brain imaging study is published in the July 13 issue of Science by researchers from the University of Michigan Health System and School of Dentistry. It is the first to combine sustained induced pain with simultaneous brain-scan monitoring of a key neurochemical system and the self-reported pain ratings of human participants. All participants gave written informed consent and were aware that the experiment involved pain.

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 study found that the onset and slow increase 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 study 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," says lead author Jon-Kar Zubieta, M.D., Ph.D., assistant professor of psychiatry and radiology at the U-M Medical School and assistant research scientist in the Mental Health Research Institute.

The body-brain pain connection occurs on many levels. Even as our bodies respond to the sensation of pain and our brains integrate that sensation with our knowledge of the environment in which it occurs, the brain produces chemicals - the endogenous opiods - that lessen our perception of painful nerve signals, protecting us from fully feeling them. The way the chemicals produce this effect is similar to the action of some pain medications.

Opioids also play a role in feelings of pleasure and reward, and in responses to stressful situations, and may even be involved in the "runner's high" felt during strenuous exercise.

More recently, specific endogenous opioids such as the so-called endorphins and enkephalins have been found and studied, as have the various kinds of opioid receptors that dot the surface of brain neurons. Studies have even pieced together the chemical cascade within a neuron that results from the binding of an opioid molecule to its receptor and triggers the neuron to stop sending a pain message - an effect known as antinociception.

The mu opioid receptor in particular has been found to be a major target for both the body's own painkillers and for drugs from outside the body, such as heroin, morphine, methadone, synthetic pain medications and anesthetics. All are capable of numbing pain, and, in the case of drugs of abuse, produce pleasurable sensations during use.

At the same time, medical imaging studies have revealed which areas of the brain most respond when a person is experiencing the sensation of pain, some of which also have high concentrations of mu opioid receptors. This understanding provided a foundation on which the U-M study sought to build.

But instead of looking at the general activity of the brain, the researchers set out to watch the response of the chemical systems involved in suppressing the experience of pain - namely, the opioid system - and to relate its function to the volunteers' subjective reports of what they felt.

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 gave 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 chose first to study prolonged jaw pain, mimicking the chronic condition called temporo-mandibular joint disorder. To simulate TMJ's symptoms, they devised a way to inject high-concentration salt water directly into each volunteer's jaw muscle, causing a painful sensation that continued only as long as the water was injected. This approach ensured that the procedure was safe. A placebo solution that does not cause pain was also 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 with chronic pain conditions like TMJ.

After injecting the radiolabeled tracer into the blood and allowing it to spread to the brain, the researchers placed each volunteer in the PET scanner and injected either the placebo or the pain-inducing solution into the jaw muscle. The study's double-blind design meant that neither the researchers nor the volunteers knew which solution was first, but all volunteers got both.

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, says 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 says. "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 regions most significantly affected were exactly those involved in the affective, or emotional, responses, and those primarily involved in processing sensations.

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 says. "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."

The researchers now hope their findings will lead to more understanding of chronic pain and ways to treat it. As the population ages and more people grapple with arthritis and other chronically painful conditions, this knowledge will become more important. So will information on variation among individuals' pain response, which may help clinicians tailor treatment or learn why certain chronic pain conditions such as TMJ and fibromyalgia are more common in women.

Besides Zubieta, the research team included: Yolanda Smith, M.D., of the Department of Obstetrics & Gynecology; Joshua Bueller and Yanjun Xu of the Department of Psychiatry and MHRI, Michael Kilbourn, M.D., Douglas Jewett, Charles Meyer, Ph.D., and Robert Koeppe, Ph.D., of the Department of Radiology, and Christian Stohler of the School of Dentistry.

The research was funded by the National Institute of Dental and Craniofacial Research of the National Institutes of Health. All research protocols were reviewed by the U-M's Institutional Review Board.

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