U.S. And Canadian Researchers Link Gene To Pain Relief In Redheaded Women

March 27, 2003

GAINESVILLE, Fla. — The jury is still out on whether blondes truly have more fun, but if the latest medical research is any indication, it’s redheads who could have all the luck: A potent painkiller appears to work better in women who carry a gene associated with red hair and fair skin, report University of Florida and McGill University researchers.

The study, published this week in the Proceedings of the National Academy of Sciences, is the first to link the presence or absence of a specific gene with differences in how men and women respond to a painkilling drug. The findings lend credence to the idea that scientists could someday maximize the effectiveness of prescription medicines for patients on the basis of specific genes.

“We’ve known for some time that there appear to be differences in the way men and women respond to certain painkilling drugs,” said Roger Fillingim, an associate professor in UF’s College of Dentistry and a study co-investigator. “The findings of our study are significant because we have now demonstrated that there are, indeed, different biological pain modulation processes at work in women than in men and that a specific gene seems to control these processes.”

For many years, physicians have anecdotally reported that redheads are more difficult to anesthetize and effectively manage with drug therapies.

“Clinicians will tell you there is something different about the way redheads respond to drugs,” Fillingim said.

Until now, however, scant scientific evidence existed to support those notions, he said.

In the study’s initial stages, researchers used a sophisticated statistical method to identify, or map, a gene that might be responsible for affecting how female mice respond to pain. The gene, melanocortin-1 receptor, or Mc1r, has long been identified as the gene responsible for red hair and fair skin in humans.

The study focused on a strain of mutant mice that carries the Mc1r gene, expressed by a distinctive yellow-orange coat. The sex differences in the painkilling effect of certain drugs in normal “wild-type” mice already were established.

“We also had identified the basic location of the gene in the mouse genome that may be responsible for this sex difference,” said Jeffrey Mogil, a neuroscientist at Canada’s McGill University and the study’s lead investigator. “The Mc1r gene is in the area, the end of chromosome 8, of the gene we were looking for, so we thought about using these mutant mice in our study.”

The scientists studied how these genetically unique “redheaded” mice responded to a painkiller similar to the drug pentazocine, comparing their reactions with those of other mice who did not carry the Mc1r gene.

Researchers found the drug had the expected sex-differentiated effect in normal mice and the male mutant mice, but that the mutant female mice with the variation of the Mc1r gene did not respond in the same way as the normal female mice. The next step was then to test the drug in humans with variants of the human Mc1r gene.

UF researchers recruited 42 healthy men and women on the basis of their hair color and skin type. Twelve men and nine women were categorized as nonredheads, and an equal number were redheads. Study participants were asked to rate the severity of their pain on a scale of 0 to 100 after receiving brief, repeated impulses of heat on their forearms before and after receiving an injection of pentazocine, marketed in the United States under the trade name Talwin. They also rated the intensity and unpleasantness of their pain on a scale of 0 to 20 at 60-second intervals while a blood pressure cuff was tightened around their left arm for up to 15 minutes.

Researchers discovered that redheaded women who carried two versions of the Mc1r gene experienced much greater pain relief from the drug compared with all other test subjects.

Currently, doctors select the drugs they prescribe and their dosages on the basis of a patient’s weight and medical problem. This approach does not take into account various other factors that may influence a patient’s response to a drug, Mogil said.

“Our study indicates pharmacogenetics – or the way genes affect drug response – can provide prediction of drug response in patients given the status of a relevant gene,” Mogil said. “This means, in the future, we may be able to look at a person’s genetic characteristics to prescribe drugs that work best for that individual patient and at doses most appropriate.”

Study researchers already are examining the sex-specific effects of a more commonly used group of morphine-like drugs called mu-opioids on redheaded mice. Morphine-like drugs are the type most commonly used to treat severe pain.

“We have preliminary evidence in mice that the Mc1r gene is relevant, in a sex-specific way, to morphine,” Mogil said.

Human studies are under way to further explore the relationship between the Mc1r gene and sex differences in drug responses.

“The ultimate goal would be to do a blood test on somebody, look at their genetic makeup as well as other chemical, biological and physical characteristics, plug all that information into a computer, and the computer would print out a sheet that says, ‘Okay, this drug, at this dose, is going to provide this patient the best relief from pain’,” Fillingim said.