A gene linked to red hair and fair skin is reportedly responsible for sex differences in pain perception. Previous research reported the existence of a female-specific pain pathway that involves an analgesic (pain killer) called kappa-opioid. Its receptors apparently work only in women.

Neuroscientist/behavioral pharmacologist Jeffrey Mogil, an endowed professor pf psychology at McGill University in Montreal, is senior author of an article in the Proceedings of the National Academy of Sciences (PNAS), released online March 25, 2003. Its title: "The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans."

"While we believe pain is the same in all women of all hair colors," Mogil told BioWorld Today, "our finding in this PNAS study shows that women with red hair respond better to the pain-killing drug pentazosine than anyone else - including men."

Using a genome-screening technique called quantitative trait locus mapping (QTL), Mogil and his co-authors identified a candidate gene that may be responsible for this sex difference. "Interestingly," he observed, "this gene, called Mc1r [short for melanocortin-1 receptor] was first associated not with neurological function, but with pigmentation. Variant alleles of Mc1r cause red hair and fair skin in humans.

"We tested the effects of the kappa-specific analgesic on mutant mice with an inactive variation of Mcr1r, analogous to the redhead' variation in humans. Although we saw typical sex differences in analgesic effects in normal mice, these differences disappeared in the mutants. We then tested it clinically using the kappa analgesic, pentazocine, on male and female human volunteers. Several Mc1r gene variations caused different hair colors and skin types in these participants. The gene variations did not affect analgesic response to pentazocine in men, but produced a heightened response in redheaded, fair-skinned women. These results suggest," Mogil continued, "that Mc1r modulates a kappa-specific pain pathway - in females only."

Painkiller Works Better In Redheaded Women

"We didn't find that actually," he added. "Overall we found no evidence that this analgesic worked any better in women than men. What we did find is that it worked better in redheaded women than everyone else.

"There are in fact redheaded mice," Mogil noted. "Some mutants that we used in the PNAS paper are in every reasonable respect mouse redheads. Except that there's a species difference in their pigments, such that the murine equivalent to red is yellow. So these guys are essentially beige when they should be black. But in every sense they count as redheaded. They have nonfunctional melanocortin-1 receptors, just like human redheads."

The PNAS paper described in detail the in vivo mouse and human experiments the McGill team conducted. "Everything in this mouse study," Mogil recounted, "was done using kappa-opioid analgesic. In mice, it was just the standard hot-water-tail withdrawal test. We very lightly restrained the mouse, dipped its tail halfway into hot water, 49 degrees Celsius. It's hot enough so that you'd be able to keep your finger in for about as long as the animals do - four, five or six seconds. We measured it to the nearest 0.1 second, scoring the number of seconds it takes them to flick their tails out of the water. When they've had enough, when it's gone from warm to hot, they remove their tail from the situation and that's all over. We gave them an analgesic and tested them again later, 15, 30, 50, 60 minutes after getting the drug how much longer they can keep their tail in under the influence of the pain killer.

"We contracted out our human tests in Florida," Mogil explained, "because we don't test people in our lab, only mice. Those humans numbered 42 healthy, non-Hispanic white volunteers, ages 18 to 41 - including 12 male and nine female nonredheads and as many redheads. Two different tests were conducted, with multiple different measures. The thermal test involved a metal heat source placed on the forearm - a very standard method. The other test, which involves administering the kind of pain you would have if you put on a blood-pressure cuff too tight. The subjects rated how painful the test was. Once they didn't like it any more they requested stopping their test, indicating tolerance.

"The upshot of both human trials," Mogil summed up, "is that there was no difference in hair color and the amount of pain reported before the drug. The pentazocine analgesic worked better in redheaded females, specifically in women having two variant alleles at the melanocortin-1 receptor gene."

What Does Mogil's Group Do Next?

"A number of places," he said of the next steps. "The experiments in mice suggest that this candidate gene detected by QTL mapping might actually be relevant to morphine analgesia as well as the kappa-opioid. So we are continuing those experiments, and actually looking at morphine analgesia volunteers now - again, redheaded women and men and nonredheaded women and men. If this gene proves to be involved in morphine analgesic response, that's a bigger deal yet, because then that would be relevant to virtually all analgesics in common use today. Over-the-counter pain-killers are a different story.

"And I have a lot of work to do," Mogil went on, "trying to figure out the neural circuitry here in the mouse, where the melanocortin-1 receptor is exactly, what it's connected to upstream and downstream. So there's a lot of anatomy and microinjection work to be done. Finally, there was a report from a meeting of anesthesiologists in October 2002 suggesting that redheaded people are less sensitive to anesthesia. We are testing our mice for that and finding that that's probably true. So one interesting thing would be to determine the exact connection between anesthesia and kappa analgesia.

"In terms of our study, it is not entirely true that clinical decisions whether or not to use these drugs ought to be made based on these data. But it does suggest of course that if men and women actually do use separate neural circuits to modulate pain, then the industry might be able to come up with drugs that literally would work on one sex but not the other.

"This is an important demonstration," he observed, "that mouse genetics can be translated into human genetics in the span of a single study. We think," he concluded, "that it illustrates the power of mouse genetics to learn about human genetics."