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Sex, Hormones & Genetics Affect Brain's Pain Control System

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    Sex, Hormones & Genetics Affect Brain's Pain Control System

    University Of Michigan Health System

    Sex, Hormones & Genetics Affect Brain's Pain Control System

    DENVER - We all know people who can take pain or stress much better than we can, and others who cry out at the merest pinprick. We've heard stories of people who did heroic deeds despite horrible injuries, and stereotypes about women's supposedly sensitivity to pain that don't mesh with their ability to withstand childbirth's pain.

    But what accounts for all these differences in how individuals feel and respond to pain? And why are some people, especially women, more frequently prone to disorders - like temporomandibular joint pain and fibromyalgia - that cause them to feel crippling pain day and night?

    Researchers at the University of Michigan believe many answers to these questions lie in the brain -- specifically, how the brain controls our responses to pain.

    Now, after several years of using sophisticated brain-imaging techniques that let them see chemical activity in the brain while pain is occurring, the U-M researchers believe they've pieced together some clues to individual pain variations. And what they've found has surprised even them, as they will report on Feb. 18 at the annual meeting of the American Association for the Advancement of Science.

    At AAAS, the team will report that gender, sex hormones like estrogen, and genes appear to play a big part in how individuals' bodies, and emotions, react to pain.

    In fact, their newest preliminary data suggest that variations in women's estrogen levels -- like those that occur throughout the monthly menstrual cycle, or during pregnancy -- regulate the brain's natural ability to suppress pain.
    When estrogen levels are high, the brain's natural painkiller system responds more potently when a painful experience occurs, releasing chemicals called endorphins or enkephalins that dampen the pain signals received by the brain.
    But when estrogen is low, the same system doesn't typically control pain nearly as effectively.

    Those results build on other recent data the team has gathered on gender-based and genetic differences in pain response. And they hope their effort to understand pain may aid studies about the brain's response to many other kinds of stressors.

    "Pain has both physical and emotional components. If prolonged, it also becomes a stressor that influences our emotional states," explains lead researcher and U-M neuroscientist Jon-Kar Zubieta, M.D., Ph.D. "And the interplay of gender, hormones, genetics and brain neurochemistry appears to induce our individual response to it."

    Zubieta and his colleagues at the U-M Mental Health Research Institute have spent several years using positron-emission tomography, or PET, brain imaging to study pain. They have focused on the activity of one of the principal natural painkiller systems in the brain, known as the mu-opioid neurotransmitter system, that mediates the effects of endorphins or enkephalins.

    When pain or other sources of stress become significant and threatening, groups of cells in the brain release chemicals called endogenous opioid chemicals, commonly known as endorphins or enkephalins. The endorphins bind to receptors on nearby brain cells and regulate how the brain interprets and regulates the pain-related signals those cells are sending to one another. The effect is called antinociception, because the neurotransmitters typically suppress the pain response, as opposed to nociception, which is the actual perception of pain.

    Mu-opioid receptors are found throughout the brain, but are concentrated in areas that scientists know to be involved in our physical and emotional responses to stressors, including pain. Natural endorphins aren't the only thing that can bind to them; so can painkiller medications such as morphine, some anesthetics, and illegal drugs such as heroin. No matter what's binding to the receptors, the effect is a quelling of pain and our response to it.

    In July, 2001, the U-M team published a paper in the journal Science that contained the first glimpse of the brain's mu-opioid system in action, and confirmed the system's important role. Using a radioactive tracer attached to a molecule that only binds to mu-opioid receptors, they showed on PET scans that the endorphin systems became activated in the brains of 20 volunteers who were subjected to moderate levels of pain in their jaw muscle over 20 minutes.

    That activation of endorphin release also corresponded with a drop in the volunteers' perceived pain and pain-related emotions - thereby linking the physical response with the emotional one.

    Armed with the ability to see the brain's response to pain, Zubieta's team began looking at how that system handled pain in people of different genders, hormone levels and genetic makeup.

    They used the same double-blind, placebo-controlled jaw pain model, induced by a harmless injection of salt water into the masseter muscle, for all the studies. The injection is meant to simulate a condition called temporomandibular joint pain disorder, but is also a useful human model of sustained pain, and physical and psychological stress. Subjects rate their pain often during the PET scan, and the injection is controlled to keep the pain level the same at all times, so that unnecessary suffering is avoided. Subjects fill out standardized questionnaires after the scan, about how the pain made them feel.

    In June 2002, the team reported in the Journal of Neuroscience the first findings that some of the differences between individuals in response to pain are governed by the mu-opioid system. In the study, 14 men scanned before and during jaw pain showed increases in endorphin release in certain brain areas during the painful state, as shown in the previous study. But most of the 14 women studied actually showed a reduction in endorphin release. The women also reported feeling more intense pain, and more pain-related negative emotions, than the men.

    Zubieta notes that all the women were studied at a time in their menstrual cycle when levels of estrogen and progesterone were lowest.

    This gender difference in pain response makes sense in light of what is already
    known about women and pain, says Zubieta, an associate professor of psychiatry and radiology at the U-M Medical School. "Women experience chronic pain syndromes more frequently, often in tandem with stress-related mood disorders, and they are also more sensitive to the effects of opiate drugs," he explains.

    "This may be due to a difference in their capacity to activate their pain-response systems when estrogen or progesterone are low."

    But to understand women and pain, it turns out, one must look at the influences that hormones may have on these pain-control systems. For the 2002 paper, the researchers had only studied women in the early follicular phase of their menstrual cycles, when estrogen levels are lowest, in order to make sure results were as consistent as possible from woman to woman. None of the women in the study was taking hormonal birth control, and all had ovulated the previous month.

    For their latest pilot study, the team scanned healthy women once during their early follicular phase, and again during that same phase in another month -- after they had been wearing an estrogen-releasing skin patch for a week. The patch made their levels of estrogen rise to levels normally seen during later parts of the menstrual cycle. This allowed the team to study estrogen's effect without the effects of other hormones, such as progesterone, that normally increase along with it.

    Scans made without the painful jaw stimulus showed that under high estrogen conditions, the number of available mu-opioid receptors, where endorphins would dock in case of pain, increased in several pain- and stress-controlling areas of the brain.

    When the painful jaw injection was given, the effect of the estrogen on the capacity to activate this painkiller system was also striking. Instead of the low or absent activation of the mu-opioid system seen in women during low-estrogen conditions, the same women under high-estrogen conditions showed a marked increases in their ability to release endorphins and activate the receptors.

    In other words, they had a response to pain that was more like the men in the previous study. And the effect was seen in multiple brain areas involved with the perception and regulation of pain, and of other stressful and emotionally significant stimuli.

    These data, now being confirmed in larger groups of women, hint at the powerful effects of female hormones on pain and stress responses, Zubieta says.

    Also tantalizing are data that Zubieta will discuss briefly at the AAAS meeting, on genetic findings that he and his U-M colleagues are preparing to publish in Science. They have found that variations in a gene involved in clearing away another brain chemical - dopamine - may strongly influence a person's pain
    tolerance, whether they're male or female.

    Since the dopamine system and the mu-opioid system are known to be linked, the discovery may help explain even more of the differences between people in pain response.

    "All of this work is helping tell us how important individual differences are in the experience of pain and other significant stressors," says Zubieta. "Our findings and those of other groups underlie the need to think about pain, particularly prolonged or sustained pain, as the result of complex interfaces between injury and our own capacity to regulate its severity and significance."

    He continues, "Furthermore, many of the regions involved in the regulation of pain perception are also implicated in how we respond to many other threatening or stressful stimuli. As a result, chronic pain conditions should also be investigated in the framework of these complex processes and interactions, including gender, genetic vulnerabilities and other environmental factors."

    Zubieta notes that other researchers from around the world are also looking at how pain, emotions, physical symptoms and environmental stresses are all intertwined. Several of them from Canada, Sweden and the United States will present at the same AAAS symposium, "Systems Integration and Neuroimaging in the Neurobiology of Pain," from 8:30 to 10:30 a.m. on Tuesday, February 18.

    Scientists Find 'Ouch' Gene

    Scientists Find 'Ouch' Gene
    Thu Feb 20,11:54 PM ET Add Health - HealthScoutNews to My Yahoo!

    By Jennifer Thomas
    HealthScoutNews Reporter

    THURSDAY, Feb. 20 (HealthScoutNews) -- If you find yourself whining over a paper cut or moaning over a stubbed toe, blame your genes.

    In Yahoo! Health:

    Visit the Heartburn and
    GERD Center

    The difference between a wimp and a tough guy (or girl) is due in part to a tiny variation of a single gene, a new study says.

    In a second report, researchers have identified how neurons form "memories" of past pain. The research could help to explain why some people experience chronic pain even after the injury or inflammation that sparked the pain has subsided.

    The discoveries, which appear in the Feb. 21 issue of Science, add to a growing body of research finding that an individual's perception of pain is largely dependent on his genes and brain chemistry.

    "We know as clinicians that that there are certain individuals who, given the same exposure to pain, experience it chronically and forever, while there are those who get over the pain quickly," says Dr. Charles Argoff, director of the Cohn Pain Management Center and an assistant professor of neurology at New York University School of Medicine.

    "This work is fantastic in that it starts to show that there could be underlying genetic differences that may explain why some people, given the same experience, never get rid of the pain or experience it longer while some barely experience it at all," he adds.

    In the study on "pain memories," researchers from Germany and Austria knew from previous research that when a certain group of neurons in the spinal cord are stimulated by pain-related matter called "substance P," abnormally enhanced sensitivity to pain can result.

    The researchers determined that the activation of a key set of receptors creates conditions that promote the strengthening of the connections among the neurons, leading to a permanent enhancement of the pain-processing pathways, and, therefore, increasing sensitivity to even the most minor pain.

    In the second study, which focused on the genetic differences of pain perception, researchers injected 15 men and 14 women ages 20 to 30 with salt water. The injection simulated the pain someone would feel if he had a chronic condition called temporomandibular joint pain disorder.

    During the experiment, the study participants were asked to rate their pain every 15 seconds while researchers monitored their brain activity using positron-emission tomography, or PET scans. The participants were also asked to fill out a detailed questionnaire about their perception of pain and their level of emotional distress after the study.

    Researchers found study participants who had a single variation on the COMT (catechol-O-methyl transferase) gene experienced more severe pain and were more troubled by the experience.

    Researchers focused on the COMT gene because it contains enzymes that control the metabolism of the neurotransmitters dopamine and noradrenaline. The enzymes act as a sort of brain janitor, breaking down and metabolizing dopamine and noradrenaline, says Dr. Jon-Kar Zubieta, lead author of the study and an associate professor in the departments of radiology and psychiatry at the University of Michigan.

    Each person has two copies of the COMT gene, inherited from each parent. The COMT gene carries one of two amino acids: valine ("val"), or methionine ("met"). Therefore, you can have one of three combinations: val-val, met-met or met-val.

    People with the val-val combination make powerful COMT that mops up dopamine rapidly, Zubieta says. People with the met-met combination make poor COMT that can't clean up the dopamine in their brains very well.

    Those with one copy of each gene variety, the met-val combination, fall somewhere in the middle. The met-val combination is the most common, Zubieta says.

    Animal studies have shown that when the dopamine system is highly active, the brain reduces its production of chemicals called enkephalins, Zubieta says. Enkephalins, which are part of the body's pain-control system, regulate and suppress painful or stress-related signals in the brain.

    Zubieta and his colleagues found that people with the val-val combination were able to activate the brain's painkilling system better than those with the met-met combination.

    Therefore, people with the val-val combination were able to tolerate the most pain, while those with the met-met had the most pronounced response to pain. As researchers suspected, people with the met-val combination fell in between.

    "A single gene can impose how your body responds to pain and controls pain," Zubieta says.

    The discoveries open the door to identifying other pathways that impact or pain perception and emotions, Argoof says.

    More information

    For help coping with chronic pain, check out the American Pain Foundation or the American Chronic Pain Association.

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