MU OPIATE RECEPTOR. This 3D model shows the receptor's helical arms, which reach out and embrace natural pain killers and addictive opiates alike. People with more receptors feel less pain.

President Clinton may feel your pain--but that doesn't mean it hurts him very much. Indeed, people have very different tolerance levels; the same needle may feel like a pinch to one person and an ice pick to the next. Certainly part of how people perceive pain depends on expectations, fears and other psychological influences. But scientists have now gathered more evidence that pain sensitivity has a strong physical basis as well.

"Many assume the way people respond is voluntary. 'Just put up with it' has been a common recommendation for years," notes George R. Uhl, the lead researcher behind the latest results. "But now people can think of pain as a genetically regulated problem."

Uhl and his colleagues, Ichiro Sora and Zaijie Wang, of Johns Hopkins University and the National Institute on Drug Abuse (NIDA) zeroed in on the gene encoding the mu opiate receptor--sections of which they first identified a decade ago. This receptor binds not only with the body's natural pain killers, endorphins, but also with morphine and other opiate drugs, such as heroi. What they found were striking variations among individuals, which they presented at a National Academy of Sciences' colloquium last December and reported in the July 6th issue of the organization's Proceedings.

Image: J. JAMES FROST, Johns Hopkins Hospital

PET SCANS. Mu opiate receptors in the human brain are concentrated in the thalamus (red), involved in pain, the cerebral cortex (green), the visual cortex (violet) and the basal ganglia (yellow and orange), which coordinates movement and emotion. The number of receptors varies dramatically among individuals, probably owing to genetic differences.

In their initial round of experiments, the group compared stretches of the mu opiate gene in eight different strains of mice. The key differences they uncovered lay within regions of the gene that regulate how many receptors are made. Those animals with more active forms of the gene had higher numbers of mu receptors in their tissues--and higher tolerances for pain.

Uhl and crew then produced mice that had half the normal number of opiate receptors and as a result, experienced greater discomfort when exposed to a standard mildly painful stimulus. Knockout mice, which completely lacked the gene and so manufactured no mu opiate receptors, were all the more sensitive. The work further showed that the fewer receptors, the less responsive the animals were to morphine.

The next step was looking at humans. PET scans have demonstrated that some individuals have twice as many mu opiate receptors in certain brain regions as others. And additional research has uncovered gender differences: women appear to have more kappa opiate receptors, which also bind with endogenous pain killers. But it was unknown if there were actual genetic discrepancies.

To find out, the team looked at several hundred human mu opiate genes, lumping together their own studies of several dozen volunteers from pain or opiate addiction clinics with studies from other labs. The analysis is still ongoing, but so far, the genetic variations they have seen seem to be of mice and of men. The "business end" of the gene--which codes for the actual receptor--was fairly constant in humans, suggesting that individual differences exist within the gene's regulatory areas. "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," Uhl noted.

The results provide more than just comfort for cry babies. They could help scientists develop pain medications that are tailored to each individual patient's genetic makeup. And they could make it possible to predict a person's individual risk for developing a drug addiction.