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Thursday, Feb. 27, 2003

NATURAL SELECTIONS

GENE-CODED TOLERANCE

How much pain can your brain take?


Japanese TV became famous abroad in the 1980s and created an image of Japan for outsiders that still lingers. The shows were the gaman taikai (endurance contests), where members of the public carried out tasks in which they suffered pain: The winners were the ones who endured the most.

I'm sure many of us remember the men doing handstands against aluminum in blazing sunshine, while staff focused the sun on the men's nipples with magnifying glasses.

Shows with similar objectives (to entertain by showing people in pain) are still common on Japanese TV. You might see, for example, women in bikinis being immersed in tanks of scalding water and emerging lobster pink. Pain appears to have a different status in Japanese culture than it does in the West.

The reasons for this, for why people are told "gaman dekiru (you can endure)" so often in Japan, are complex and cultural and beyond the scope of this column. But research published in Science last week suggests that variations in a certain gene may be responsible for differences in how individuals respond to pain and other stimuli, such as emotional stress.

The discovery adds to evidence suggesting that variations in individuals' responses to pain are mainly due to biological factors affecting the brain, specifically the operation of its natural pain-control systems.

University of Michigan neuroscientist and lead author Jon-Kar Zubieta headed a team that showed that a small variation in the gene that encodes the enzyme 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 (caused by injecting saline into the masseter muscle), 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 the COMT enzyme they made.

COMT 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. These variant enyzmes are known as methionine or valine.

The form of the enzyme containing methionine (the "met" form) is much less active in the brain than the one containing valine (the "val" form). 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," said Zubieta. "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."

The team used a type of brain-imaging called positron-emission tomography, in combination with a radioactive tracer that lets them see how the brain is activated in response to pain. Twenty-nine subjects rated the intensity of their pain during the PET scan.

The study's findings surprised Zubieta and his coauthors from the University of Michigan and the National Institute of Alcohol and Alcoholism. But, he said, they make sense given COMT's role.

The COMT protein is a sort of brain janitor, cleaning up the spaces between brain cells after neurotransmitters finish sending signals. COMT does this by breaking down the brain chemicals dopamine and noradrenaline.

Those with two copies of the val form of the gene make powerful COMT that mops up dopamine rapidly. People with two copies of the met form of the gene make poor COMT that 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 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 relevant to our lives.

When the dopamine system is highly active, the brain reduces its production of endorphins. Endorphins are part of the brain's painkilling 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. (Heroin also functions in this way, by binding to these receptors, blanketing pain.)

Aware that the brain's ability to activate the painkilling 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.

"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," Zubieta said.

So are the winners of the Japanese endurance shows people with two copies of the val form of the COMT gene, able to withstand more pain than others? Of course we don't know.

However, there is another possible explanation for why they won. In 1999, researchers in the United States reported that student volunteers thinking of a favorite sexual fantasy were able to endure more pain than those thinking neutral thoughts, such as walking to school.

Perhaps the winners of endurance contests use a similar strategy to block out the pain. One thing: Just don't tell us what those fantasies are.

Rowan Hooper welcomes comments at rowan.hooper@tcd.ie


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