Your epigenetics can be a pain

There are times when science is a painful experience. My most excruciating moment in science involved a heated electrode placed on my bare leg. This wasn’t some sort of graduate school hazing ritual. I was a volunteer in a study to determine how we process feelings of pain. As part of the experiment I was exposed to different levels of heat and asked how painful I thought they were.

When the electrode was removed, I eagerly asked how my pain tolerance compared with that of others. I secretly hoped that I was some sort of superwoman, capable of feeling pain that would send other people into screaming fits and brushing it off with a stoic grimace. It turns out, however, that I was a bit of a wuss. Ouch.

I figured I could just blame my genes. About half of our susceptibility to pain can be explained by genetic differences. The other half, however, remains up for grabs. And a new study published February 4 in Nature Communications suggests that part of our susceptibility to pain might lie in chemical markers on our genes. These “notes” on your DNA, known as epigenetic changes, can be affected by environment, behavior and even diet. So the findings reveal that our genetic susceptibility to pain might not be our destiny.

Tim Spector and Jordana Bell, genetic epidemiologists at King’s College London, were interested in the role of the epigenome in pain sensitivity. Epigenetic changes such as the addition (or subtraction) of a methyl group on a gene make that gene more or less likely to be used in a cell by altering how much protein can be made from it. These differences in proteins can affect everything from obesity to memory to whether you end up like your mother.

Bell and her colleagues looked at 50 pairs of identical twins, took some blood, and dug into their epigenomes. While most pairs of identical twins have pain sensitivities that are, well, identical, these 50 pairs showed substantial differences in pain threshold (the point at which you go “ow!”). Because identical twins have almost completely identical genomes, variations in genetics could not account for the differences in pain sensitivity.

Instead, the scientists found that the differences in pain sensitivity were associated with different levels of methylation on nine different genes. The one that stood out the most was the pain-associated gene TRPA1. Twins with increased methylation in the promoter area of TRPA1 showed decreased sensitivity to pain. The promoter area serves as a gatekeeping mechanism for the gene, and increasing methylation there decreased how much the gene could be used to make protein. Decreased methylation in this area, on the other hand, was associated with more TRPA1 and made for a pain-resistant superstar. Relative to their twin, anyway.

This may mean that your pain sensitivity is not destiny. “The epigenetic changes are reversible,” Spector explains. “Twins are likely to be conceived with the same methylation pattern and through life that has altered.” If scientists can discover how to alter the epigenetic markers on your pain-associated genes, they could uncover ways to make us less sensitive to pain. “Potentially, we could change our pain sensitivity,” Spector says. “Unfortunately at the moment we don’t know exactly how.”

That’s because this is all associations between genes. No one knows what causes the changes in methylation that make you more or less sensitive to pain. But studying that relationship is a great place to start. “We hope that these results will help other researchers realize that epigenetic changes to pain genes alter pain sensitivity,” Specter says, “and we hope pharmaceutical companies will work on some of these potential targets.” Companies looking for a more effective painkiller can now focus on changing the methylation on genes like TRPA1, or focus on TRPA1 itself. 

Inna Belfer, a human pain geneticist at the University of Pittsburgh, says the study opens up many options for the future of pain research. “Five years from now,” she says, “we might have a clear picture of the pain perception genome and epigenome, we could know all the genetic factors that influence the pain system.”

Belfer is especially pleased that Bell and colleagues were able to show that the epigenetic findings do not differ between blood and brain tissue, using samples of each from two patients who donated their tissues to science after death. That means that future studies will be able to use blood to look at pain epigenetics. This is far better than trying to get brain tissue, which usually requires the death of your study subject.

So not only do researchers have a new target for developing pain medications, but they also have a less invasive way to study pain-related epigenetics. With any luck, this will make future drug discovery … less of a pain.