For years, the brain chemical dopamine has been thought of as the brain's "pleasure chemical," sending signals between brain cells in a way that rewards a person or animal for one activity or another. More recently, research has shown that certain drugs like cocaine and heroin amplify this effect -- an action that may lie at the heart of drug addiction.
Now, a new study from the University of Michigan adds a new twist to dopamine's fun-loving reputation: pain.
Using sophisticated brain-scanning and a carefully controlled way of inducing muscle pain, the researchers show that the brain's dopamine system is highly active while someone experiences pain -- and that this response varies between individuals in a way that relates directly to how the pain makes them feel. It's the first time that dopamine has been linked to pain response in humans.
The finding, published in the October 18 issue of the Journal of Neuroscience, may help explain why people are more likely to acquire a drug addiction during times of intense stress in their lives. It may also yield clues to why some, but not other chronic pain patients may be prone to developing addictions to certain pain medications. And, it gives further evidence that vulnerability to drug addiction is a very individual phenomenon -- and one that can't be predicted by current knowledge of genetics and physiology.
"It appears from our study that dopamine acts as an interface between stress, pain and emotions, or between physical and emotional events, and that it's activated with both positive and negative stimuli," says senior author Jon-Kar Zubieta, M.D., Ph.D., professor of psychiatry and radiology at the U-M Medical School and a member of the U-M Molecular and Behavioral Neuroscience Institute and U-M Depression Center. "It appears to act as a mechanism that responds to the salience of a stimuli -- the importance of it to the individual -- and makes it relevant for them to respond to."
The study, which involved 25 healthy men and women, showed that dopamine was active in areas of the brain region known as the basal ganglia, the same region where it has been observed to respond to positive stimuli, such as food or sex.
But when the researchers induced pain in the volunteers' jaw muscle, and asked them to rate different aspects of how they were feeling, differences emerged in specific sub-areas of the basal ganglia. For example, the more a person rated the pain as causing emotional distress and fear, the more dopamine was released in the area known as the nucleus accumbens -- the same region implicated in drug addiction.
That effect persisted even after the researchers controlled for the negative emotional effects caused by the actual research setup, which included a needle inserted into a large jaw muscle, and the expectation of pain and repeated questioning.
Similarly, dopamine release in two other areas of the basal ganglia -- the putamen and caudate nucleus -- was strongly correlated with the rating of how intense and unpleasant the pain itself was on a scale of 0 to 100. The authors concluded that in some areas of the basal ganglia, dopamine was involved in the assessment of pain itself, while in the ventral area, or nucleus accumbens, it was related to the emotional experience of pain.
The study used positron emission tomography, or PET, scanning that allowed the researchers to calculate the level of dopamine activity by measuring the percentage of dopamine receptors on the surface of brain cells that were active. To do this, they used the drug raclopride, to which had been attached a short-lived radioactive form of carbon. The drug binds to the same receptors that dopamine does, so the more of it that could be seen in a specific brain area, the less dopamine was present and vice versa.
The researchers also scanned each volunteer's brain using magnetic resonance imaging (MRI) in order to create a precise map of the brain's structure, and combined that with their PET scans to find the exact areas of dopamine activity.
The volunteers answered questions from two standardized questionnaires repeatedly both in a control (no pain) state and when their jaw muscles were being injected with harmless salt water in order to cause pain. The questionnaires measure pain and emotion in a standardized way, so that ratings can be compared over time. None of the participants had a history of medical or psychiatric illness, nor of drug addiction or dependence. The 7 female volunteers were not taking birth control pills and were scanned at the same point in their menstrual cycles.
In addition to the differences in dopamine receptor activation in certain areas of the brain across all the participants, the scans also revealed differences between individuals in the level of their dopamine response and their self-rated pain and emotional response. This kind of variation may help explain the major variation between individuals who are exposed to addictive drugs -- some become addicted to the pleasures of the "high" the drugs cause, while others do not.
"Variations in risk for drug abuse after initial exposures could be mediated by individual differences in the response of this neurotransmitter system to various forms of stress, with pain being itself a physical and emotional stressor," write the authors, led by David J. Scott, Ph.D., a graduate student at MBNI. "The dopamine system in the ventral basal ganglia may represent an important point of interaction between the neurobiologies of emotion, reward and pain regulation.
The new findings build on previous pain research by Zubieta and his team, which has shown individual variation in the rating of pain, and has visualized the brain's own painkiller system responding to pain and even to the giving of a "placebo" painkiller medication.
Now, the team is working to examine the hormonal and genetic factors that may be different between people whose dopamine systems responded differently to pain. They also have recently received funding from the National institute of Drug Abuse to study individual variation in the effects and use of opioid painkiller drugs among people with chronic pain.
In addition to Zubieta and Scott, the study's authors include Mary Heitzeg of MBNI and Psychiatry; Robert Koeppe, Ph.D., a professor of radiology and director of the PET Physics Section in the Division of Nuclear Medicine; and Christian Stohler, DMD, Dr.MedDent., dean of the Dental School at the University of Maryland and formerly of the U-M Dental School. The study was funded by the National Institutes of Health. The U-M team that performed this study is currently seeking participants for additional studies; visit http://www.umengage.org to learn more.
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