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February 26, 2003
A tiny variation in a single gene may help explain why some people can withstand pain -- or other physical or emotional stress -- better than others, researchers from the University of Michigan and the National Institutes of Health report.
And while genetics may not make all the difference between wimps and Marines, the discovery adds to building evidence that variations in individuals' response to pain are mainly due to biological factors affecting the brain and how it processes environmental stressors, including its natural pain-control systems.
In the February 21 issue of the journal Science, the team will report that a small variation in the gene that encodes the enzyme called catechol-O-methyl transferase, or COMT, made a significant difference in the pain tolerance, and pain-related emotions and feelings, of healthy volunteers.
By combining genetic testing with molecular brain imaging techniques and controlled, sustained jaw pain, the researchers were able to see how well the participants' brains controlled the pain, and how they felt as a result, depending on what forms of COMT they carried.
The COMT enzyme helps govern aspects of brain chemistry involving the neurotransmitter chemicals dopamine and noradrenaline. The gene that encodes it occurs commonly in two forms, or alleles, which make copies of the enzyme that are different only by one amino acid, either valine or methionine.
The form of the enzyme containing methionine is much less active in the brain than the one containing valine. Everyone carries two copies of the COMT gene, one inherited from each parent.
The study showed that people with two copies of the "met" form of the COMT gene had a much more pronounced response to pain than those who carried two copies of the "val" form of the gene. Those with one copy of each form of COMT had a pain tolerance somewhere between the responses of the other two groups.
"Participants who had two copies of the val form withstood quite a bit more pain than others in the study, while at the same time reporting that they felt less pain and fewer pain-related negative emotions," says U-M neuroscientist and lead author Jon-Kar Zubieta, M.D. "This common genetic variation appears to influence individuals' pain response quite noticeably, both in their neurochemical response and in their affective responses and internal affective states."
He continues, "All of this work is helping tell us how important individual differences are in the experience of pain and other significant stressors. Our findings and those of other groups underlie the need to think about pain, particularly the more physiologically significant prolonged or sustained pain, as the result of complex interfaces between injury and our own capacity to regulate its severity and significance."
The team used positron-emission tomography, or PET, brain-imaging scanning in combination with a radioactive tracer that lets them see mu-opioid receptors and how they become activated in the brain in response to a sustained pain stressor. The pain came from a carefully controlled salt-water injection into the jaw muscles of the volunteers. 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 emotional stress.
Subjects rate their pain often (every 15 sec) 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 was perceived and how it made them feel.
The study included 29 participants, 15 men and 14 women, aged 20 to 30 years. The women were all scanned during the phase of their menstrual cycle when their estrogen levels were lowest; Zubieta and his team have previously shown that estrogen affects the mu-opioid system's response.
The study's findings surprised Zubieta and his co-authors from U-M and the National Institute of Alcohol and Alcoholism. But, he says, they make sense given COMT's role.
The COMT protein is a sort of brain janitor, "cleaning up" the spaces between brain cells after chemicals called neurotransmitters finish sending signals between brain cells. Specifically, COMT metabolizes, or breaks down, the brain chemicals called dopamine and noradrenaline, also known as norepinephrine.
Those with two copies of the val form of the gene make only powerful COMT that mops up dopamine rapidly. People with two copies of the met form of the gene make only poor COMT, and can't "clean up" the dopamine in their brains very well. Those with one copy of each gene variety -- the majority of people -- make some of each kind of COMT, yielding a "normal" dopamine-metabolizing system.
Dopamine is often known as the brain's "pleasure chemical", because of its role in transmitting signals related to pleasurable experiences. But it also has a more general role, together with noradrenaline, in how we respond to many kinds of stimuli that are "salient", or relevant to our lives. And animal studies have shown that when the dopamine system is highly active, the brain reduces its production of other chemicals: the endogenous opioids, or so-called enkephalins.
Enkephalins, and their related chemicals called endorphins, are part of the brain's own painkiller and stress-response system. They regulate and suppress painful or stress-related signals in the brain by binding to proteins on brain cells called mu-opioid receptors.
Natural endorphins aren't the only thing that can bind to these receptors and kill pain; 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 typically a quelling of pain and our responses to it.
Knowing that the brain's ability to activate the pain-killing mu-opioid system falls when the dopamine system is over-active, Zubieta and his colleagues focused on the dopamine-removing COMT gene when looking at why individual people vary so much in their responses to sustained pain and stress.
Zubieta and his colleagues set out to see whether a person's COMT genotype made a difference in their pain perception. They thought that perhaps those who metabolized dopamine very well because they had two val COMT genes would also be able to activate the brain's painkilling system better than those with two copies of the met form of COMT.
The results fit the predicted effect of COMT gene variation perfectly. Participants who had two copies of the met gene form could stand less of the painful injection than those with two copies of the val form of the gene, and their brains' mu-opioid systems were less activated in many areas of the brain.
They also gave more negative results on the surveys about their feelings and their perception of their pain, yielding scores that indicated more intense feelings. On those same surveys, the participants with two copies of the val form of the gene had lower scores for their overall experiences and how they felt at an emotional level during the pain challenge.
Those with one copy of each form of the gene had results somewhere in the middle on all measures.
The differences between met/met and val/val participants in the activation of the mu-opioid system were most significant in the cingulate cortex, anterior thalamus, the thalamic pulvinar, and the basal ganglia, including the nucleus accumbens and ventral pallidum, and the amygdala. These are areas of the brain that are involved in our response to painful and emotionally important stimuli. They all help integrate multiple aspects of those experiences, to promote particular patterns of response.
The new results build on what Zubieta and his colleagues have previously shown through their studies of the mu-opioid system and pain response.
"These data also emphasize the need to understand how genes influence our behavior by examining the intermediary brain pathways and mechanisms regulated by those genes," he says. "This understanding is necessary to link how specific vulnerability factors, such as tendencies to perceive pain as more severe, or stressors as more distressing, lead to particular pathologies, such as the chronic pain conditions or other stress-related conditions, such as anxiety and depression. Examining and detailing the biochemistry of these processes can then lead to more effective treatments for these disorders."
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