Published On August 10, 2017
EVERYONE FEELS PAIN, WHETHER FROM DISEASE, TRAUMA OR AGING. But new research into pain’s underlying biological mechanisms has revealed that males and females seem to experience it differently—and pain signals may pass through the body using completely different mechanisms. These startling facts somehow eluded science until quite recently.
“Females are more sensitive to pain than males,” said Jeffrey Mogil, a neuroscientist at McGill University in Montreal, in a keynote address this spring at the annual meeting of the Organization for the Study of Sex Differences. “It doesn’t matter how you measure the pain or what kind of pain you are measuring—this has been done hundreds and hundreds of times, and that debate is pretty much over.”
For Mogil, a more important finding—and the subject of his most recent research—is how pain signals in the sexes appear to diverge in places. “Males and females are using clearly different kinds of cells and different portions of the immune system to produce what ends up being pain,” he says.
Twenty years ago, neurons were the focus of most pain research. But now scientists know that immune cells and bacteria also generate molecules that trigger pain signals. In particular, microglia—immune cells once thought to be mere “garbage collectors”of the brain—play a particularly active role. “There has been a cultural shift in thinking about the ways that microglia function,” says Michael Salter, a pain specialist and chief of research at The Hospital for Sick Children in Toronto.
Two summers ago Mogil, Salter and their colleagues showed that one kind of pain—allodynia, which is characterized by a hypersensitivity to normal stimulation—could be reversed in mice using blockers that targeted microglia. But the treatment worked only in male animals. In females, the blockers showed no effect at any dose, a surprising result that the researchers shared in Nature Neuroscience.
“If male and female mice have the same amount of allodynia, but microglia are not involved with females, they must have a different system producing exactly the same magnitude of allodynia,” Mogil says. That mechanism in female mice could use interferon gamma, a substance produced by CD8 T cells, part of the immune system that circulates in the blood. But Mogil acknowledges that the evidence for this is so far inconclusive.
Still, whatever biological systems turn out to be involved, it’s remarkable that the fact of male and female animals exhibiting profoundly different mechanisms of pain is only now coming to light. Mogil chalks up this long delay in discovery to investigators simply not looking. His survey of all mouse and rat studies published between 1995 and 2006 in the journal Pain found that “79% of the studies that used mice used male mice, a tiny fraction used females and a tiny fraction used both,” he says. And when he looked again a decade later, at papers published in 2015, he found that little had changed. “If you don’t start by using both sexes right at the very beginning of your research, that is not only scientifically idiotic and a waste of money,” he says, “it is an ethical issue as well.”
In fact Mogil believes that at least one phase 3 clinical trial for pain relief several years ago may have failed to show a benefit for the treatment because it didn’t take gender into account. The drug may have worked in men during earlier phases of the research, but that effect might have been diluted when responses in the full group of participants, including women, were analyzed. When Mogil later suggested that the trial’s research team revisit the data, separating results by sex, the company declined.
Although mice aren’t a perfect model for humans, Mogil believes that the pain mechanism he has observed in female mice that doesn’t involve microglia probably has a human counterpart. That idea would be in line with what other researchers looking at sex differences and pain have found: that some types of pain relief work only in male mice and not in female mice, and vice versa.
“We are starting to see that there are multiple mechanisms that can occur and still converge to produce pain,” says Michael Salter. “Even though the pain may feel the same in the female, the underlying biology is different.”
Mogil says the problem may be even broader. “I think it is safe to say that either there is something special about pain that makes it incredibly sex dependent, which is interesting,” he says, “or maybe everything is sex dependent, and the only reason we don’t know it is that by looking almost exclusively at males, we haven’t put ourselves, in any field, in the position to find out.”
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