For sex equality

A graphic of a blue gear containing the male symbol and a pink gear containing the female symbol.

For sex equality

Until now, experiments to understand chronic pain used mostly male mice. To scientists’ surprise, however, females react differently. Our way of understanding pain circuitry is changing...
December 20, 2016

Too many laboratories are living in the past. At one time, scientists believed that male mice were more reliable guinea pigs than female ones, who were thought to be too vulnerable to hormonal fluctuations. We now know this to be wrong. A meta-analysis of hundreds of studies confirmed that the truth was quite the opposite—the males are the more unstable ones.

At McGill University’s Pain Genetics Laboratory, both males and females have been skittering around the wood chips for a long time, and it’s thanks to this mixed-sex setting that geneticist Jeffrey Mogil and his team discovered that females and males don’t use the same immune cells to transmit pain signals to the nervous system.

This is a major discovery, especially if it’s confirmed to apply to humans, since 70 per cent of patients with chronic pain are women.

It all began when the team arrived at results that contradicted those of a study published in 2005 by the medical school at Dartmouth College in the US, according to which mice without a functional copy of the TLR4 gene felt less pain than others.

“By performing pain experiments, we noticed that the study’s results were accurate, but only for males,” says the researcher. As is customary, the study had been run only on male rodents. That was a mistake!

Jeffrey Mogil and his team thought about this issue. We know that the TLR4 gene produces a protein that is expressed by microglia, a set of immune cells responsible for transmitting pain to mice’s nervous systems. But what if it turned out that these microglial cells signal pain only in male mice? It was a revolutionary idea, since it had been assumed for nearly 20 years that whatever applied to males in this area was also true for females.

“Extraordinary claims require extraordinary evidence.” This quote by astronomer Carl Sagan was on the mind of neurophysiologist Michael Salter, who is head of research at the Hospital for Sick Children in Toronto and a pain specialist, when his colleague Jeffrey Mogil contacted him. “It was so completely the opposite of accepted knowledge for all researchers in the field … Except Jeff! So we wanted to be very certain that the results would be the same outside of his laboratory,” he explains. Well, experiments were conclusive.

Working in collaboration with Duke University, North Carolina, researchers found that the cells transmitting pain signals from the immune system to the nervous system are indeed different in male and female mice. The latter have T lymphocytes sounding the injury alarm instead of microglial cells. But both systems produce exactly the same result: they transmit the same intensity of pain! The discovery was published in Nature Neuroscience in June 2015.

The difference is clear-cut and obvious, which is rare in biology, notes Michael Salter. This means that if experiment cages had been equal-opportunity environments, this distinction would have been noticed long ago. Jeffrey Mogil says, “For 20 years, we’ve been studying microglial cells that signal pain in males. Now, we have to redo all that work to understand the circuit in females. The irony is that the female system is the “default” one. In neutered males, T cells are the ones signalling pain, like in females.

Only when the animal has enough testosterone does the mechanism switch to the microglial system. We’ve been studying the secondary circuit for 20 years!”

This probably marks the first observed instance of a mechanism using different cells depending on a subject’s sex without any relation to reproductive functions. “It may be the exception that proves the rule,” hypothesizes Jeffrey Mogil. “Or, there may be differences between the sexes everywhere in biology and we just haven’t noticed them because laboratories work only with male mice.”

So, let’s invite Minnie next time, shall we?

COULD THE SAME BE SAID FOR HUMANS?

It’s too early to tell whether women’s pain circuitry is different from men’s, like in mice. But if it turns out to be the case, it will influence research on chronic-pain drugs. Although there is currently no treatment that targets the immune cells involved, this could change one day. Researchers Jeffrey Mogil and Michael Salter are both thinking about ways to test whether the difference identified in mice is also present in humans — but that’s no easy task. “There’s no scanner that can help us check for this,” says Jeffrey Mogil. “We would need to inject a drug that would block one system or the other, which can be done only in clinical trials for the approval of such a drug. Unless we were to run tests on people with AIDS who no longer have T cells.” Even beyond the ethical questions this poses, the results may not be perfectly reliable given the poor health of those patients.

This article was translated from its original, which appeared in French in the January/February 2016 issue of Quebec Science magazine.