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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.
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U-M
neuroscientist
Jon-Kar Zubieta, M.D., Ph.D. |
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.
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| The
colorful areas in these brain scans show the areas of the brain
where higher estrogen levels made a difference in the activation
of the brain's natural painkiller system. |
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.
.jpg) |
|
Study participants were scanned as they
received a pain-causing but harmless injection of salt water
in their jaw muscle. |
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.
 |
| The
colorful areas in these brain scans show the areas of the brain
where higher estrogen levels made a difference in the availability
of receptors for the brain's natural painkiller system. |
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.
Written
by: Kara Gavin
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