The study could help put to rest the long-held assumption that pain sensitivity is a matter of mental toughness. People really do experience pain differently, doctors say -- and genetics is largely responsible.

"Many assume the way people respond is voluntary; `Just put up with it' has been a common recommendation for years," said Dr. George Uhl, a Hopkins neuroscientist who also heads NIDA's molecular neurobiology branch. "But now people can think of pain as a genetically regulated problem."

The same genetic differences also determine how much relief people get from morphine and other opiate pain killers. Many people who are highly sensitive to pain respond poorly to standard doses of pain medication.

"One of the things we hope to do with this information is try to predict who is going to need more opiate," Uhl said. Scientists might also use this knowledge to fashion drugs and gene therapies that are tailored to a person's pain sensitivity.

The research, published in this month's Proceedings of the National Academy of Sciences, builds upon a seminal discovery 27 years ago of opiate receptors in the human nervous system. Dr. Solomon Snyder, a Hopkins neuroscientist, discovered molecules on the surface of nerve cells that serve as docking points for natural opiates, chemicals manufactured by the brain to dampen pain.

Without these receptors, everyone would experience pain more intensely than they do. Opiate receptors also bind to opiate drugs such as morphine, codeine and heroin.

The recent study focused on a type of opiate receptor known as the mu receptor. Scientists discovered that slight variations in a single gene determine the number of mu receptors that appear on cells of nervous system.

Put simply, people who have lots of mu receptors feel less pain because they are able to absorb more of the brain's natural pain-relieving chemicals. For the same reason, they get faster relief from pain-fighting medications.

People who have fewer mu receptors are not as lucky.

"Things that are not painful to others are painful to them," Uhl said, "and they're not going to have their pain as effectively relieved by opiates."

Using techniques of genetic engineering, scientists bred mice that had half the normal complement of mu receptors and others that lacked them altogether. Later, the researchers measured their responses when they were exposed to gradually increasing amounts of temperature, pressure and other sources of pain.

The mice most richly endowed with mu receptors were least sensitive to pain. Those who lacked them struggled the most.

Using an imaging device known as a PET scanner, a Hopkins scientist found that humans differ by as much as 50 percent in the number of mu receptors they have. This is the same variation that accounted for different pain thresholds in mice.

Collaborators in California are testing the pain thresholds of human volunteers, asking them to do such things as place their hands in frigid water. Scientists are also studying patients who have had different responses to pain medications. In both groups, researchers are studying DNA samples to see which genetic variations are linked to higher or lower levels of pain sensitivity.

Aside from Uhl, scientists in the Hopkins study were Dr. Ichio Sora and Dr. Zaije Wang, both with the National Institute on Drug Abuse.

"Differences in the gene might affect pain therapy," said Sora, a psychiatrist.

Doctors, for instance, could use genetic information to predict if a patient will experience great pain after surgery, and prescribe higher doses of pain medication to prevent a miserable recovery, he said.

A more sophisticated approach would be gene therapy: using viruses to deliver mu receptor genes to the nervous system. Patients should then cope better with surgery and painful illnesses such as cancer. In theory, they would respond better to pain medication and feel less pain.

Solomon Snyder, chief of neuroscience, said the study shows that pain sensitivity and physical illness aren't that far apart.

"People vary in genes that determine cholesterol levels and hardening of the arteries," Snyder said. "This is really the first evidence of a specific molecular variation that determines variations in pain sensitivity."

Scientists might find a similar basis for depression and other mood disorders, he said. It's possible, he said, that people who are chronically depressed have comparatively few receptors for serotonin, a brain chemical responsible for feelings of well-being.