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For many years medical science lacked female participants. Not until the mid-1990s was it mandatory for researchers to enrol women in clinical trials. Basic science, however, still hasn't received that memo. McGill neuroscientist Jeffrey Mogil, globally known for his work on the genetic underpinnings of pain perception, is about to stir things up.
"Scientists are going to hate me." Mogil, a member of the McGill Centre for Research on Pain, is speaking about a review he co-authored with graduate student Mona Lisa Chanda that will be published in the journal Pain. For years, pain scientists have used male subjects in basic research. Of the 540 experimental studies Mogil and Chanda surveyed, the bulk — 79 percent — included only male animals. It's an important omission, says Mogil. Favouring one sex over the other when studying mouse models of human disease may do research a disservice, considering that males and females respond differently to pain.
At a young age, boys are taught to be tough, while girls are allowed a whimper or two. But as we age the differences remain. Women tend to feel more pain and feel it more intensely. Is the disparity more than just a lower pain threshold? Mogil thinks so. He's convinced that men and women are wired differently, with different genes influencing the way the pain message is carried to the brain and altering the response to some painkillers. "This is still a radical idea," says Mogil. "It's not the way that sex differences are supposed to work. It's presumed that men and women have the same system, but women have different hormones."
For years, researchers assumed that the cyclical fluctuation of female hormones would produce too much variability in their results, so they avoided using female rodents in their experiments. It turns out they were wrong. Mogil and Chanda went through their own large dataset and found no differences. "The reason everyone has in the back of their mind why they don't use female subjects is just wrong," he says. "It is just not real."
"Women have much more clinical pain than men and things work differently in them, and yet we continue to assume that our studies on male mice are going to apply to women. That's just insane." He points to his discovery two years ago of a gene involved in pain perception. Variations in this gene, the melanocortin-1 receptor, are best known for giving redheads their scarlet locks and fair skin. But it turns out that this gene also determines how females — whether mouse or human — respond to certain painkillers. "In women there is a melanocortin-1 receptor somewhere in that circuit and in men there isn't," says Mogil.
He also has preliminary evidence of other genetic differences. In an as-yet unpublished study, he tested the pain response of mice lacking three related genes, the proteins of which are expressed in the skin. These engineered mice were more sensitive to certain types of pain than their normal counterparts, but only if they were male. "What is exciting to me is that it means the pain circuit is sex-specific right from the beginning."
Fascinated by all aspects of pain, Mogil has recently shifted his focus from genetics to the social factors that affect pain. "Mice have a social life of sorts, and it affects their pain. Who is around them when they are in pain has an influence on how much pain they display." While the idea that social factors are dramatic modulators of pain isn't new for humans, it's the first time it has been shown in mice. "Now we can really get to the bottom of the neurochemistry, the genetics and the anatomy of it. It's very exciting."