July 19, 1999
Note: The Proceedings of the National Academy of Sciences, which originally slated Dr. Uhl's article for its July 20 issue, published it early, in the July 6 issue. Because our office was not informed, we planned our news release according to the original publication date.
The article is available online at www.pnas.org.
People vary greatly in their sensitivity to pain: A tetanus shot's pinprick for one person is another's misery. Now researchers at Johns Hopkins and the National Institute on Drug Abuse (NIDA) report that much of human sensitivity to pain -- and the varied response people have to opiate pain medicines -- has a genetic basis. Many of the differences in pain perception by both mouse and human, the scientists say, are likely due to variation in a single key gene.
In a report in this month's Proceedings of the National Academy of Sciences, the scientists explain why a gene coding for the mu opiate receptor, a molecule that bonds with the body's natural opiates, is the likely candidate for pain sensitivity. This same receptor also forms bonds with morphine, additionally making it a good candidate gene for the differences people experience in pain relief from morphine or morphine-like drugs.
The work should eventually result in pain drugs tailored to a person's individual genetic sensitivities -- a hallmark of genome-based therapy. It also could offer the ability to predict a person's risk of addiction to opiate drugs.
The research involves both mouse and human mu receptor genes. "It's rare to find a gene where the animal evidence for its effect is so strong or has such a clear carryover to human studies," says Hopkins/NIDA neuroscientist George R. Uhl, M.D., Ph.D., who led the study.
The researchers were the first to identify sections of the human and rodent mu receptor gene almost a decade ago. In this new work, they've focused on individual differences in the regulatory parts of the receptor gene in humans and mice -- key areas that control how many mu receptors the gene makes.
Looking at eight different strains of mice, the researchers found links between gene differences in the regulatory area and the numbers of mu receptors mouse tissues displayed. More active forms of the gene meant more receptors cranked out.
Further, the number of receptors predicted how mice would respond to a standard mildly painful stimulus: when Uhl produced mice with half the typical number of opiate receptors, their sensitivity to pain was significantly heightened. Mice with all their mu receptors knocked out were even more sensitive to pain.
Also, mouse strains with lower numbers of receptors required a greater use of morphine.
The human studies trail the mouse ones, says Uhl, but they, too, suggest the same relation between gene variation, numbers of receptors and relief of pain. The researchers pooled their studies of several dozen volunteers from pain or addiction clinics with those from other labs to report on several hundred human mu genes.
They found that the "business end" of the gene -- the part that codes for the actual receptor -- is similar from person to person. That suggests, Uhl says, that as in mice, the variations among people lie instead in the regulatory part of the gene.
PET scans in other labs at Hopkins have shown that the number of mu receptors in humans can differ dramatically: Some people have almost two times more mu receptors in certain brain areas than others.
"People have long been skeptical that pain has a genetic basis," says Uhl. They don't notice that sensitivity can vary because the differences can be subtle, he adds, "and masked by a strong emotional response to pain. Many assume the way people respond is voluntary. ‘Just put up with it' has been a common recommendation for years," says Uhl. "But now people can think of pain as a genetically regulated problem."
Pain, Uhl says, exists mainly in the brain. It occurs, in part, when something activates dedicated pain nerves in the body and spinal cord that relay impulses to the brain. But superimposed at strategic places on nerves in this system are the mu receptors. They respond to natural opiates in the body and, like mutes on so many trumpets, effectively damp down pain's intensity.
The study was supported by NIDA grants. Other researchers were Ichio Sora and Zaijie Wang, both from NIDA.
--JHMI--Related Web sites:
Go to http://188.8.131.52/DIR/MolNeuro.html for information on Uhl's research.
Access http://www.halcyon.com/iasp/terms-p.html for good definitions of pain and information on emotional aspects of pain.
Check out http://www.ampainsoc.org/bulletin/jan99/resupdate.htm for an article from the Bulletin of the American Pain Society that tells about why pain is evolutionarily useful and how it's differently perceived.
The study is reported in the July 20, 1999 issue of The Proceedings of the National Academy of Sciences, vol 96.