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

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.