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Scientists discover that male and female mice process pain differently

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This is why studying female animals is so important

Maggie Bartlett, NHGRI / Wikimedia Commons

Do women and men experience chronic pain differently? A new study suggests there may be sex differences when it comes to pain — one that may open doors for better treatment.

Mice used in basic research are almost exclusively male

The nervous system's dials for communicating chronic pain to the body work differently in male and female mice, according to a study published today in Nature Neuroscience. If this difference is also found in humans, it could lead to chronic pain treatments that are better tailored to the patient. But the most immediate impact might be in basic research — the earliest stages of work — since right now, the mice being used are almost exclusively male.

Chronic pain affects more than 100 million people in the US, which is more than heart disease, cancer, and diabetes combined. And many pain conditions occur more often in women than in men, according to the FDA. That's why figuring out how male and female mice deal with pain — and whether they do so differently than humans — is so important. After all, most medical research — including pain research — starts with mice.

In the study, researchers focused on microglia, a type of immune cell that can be found in the brain and the spinal cord. These cells are known to play a role in the "volume knob" for pain, explains Jeffrey Mogil, a pain researcher at McGill University and a co-author of the study. The knob turns way up after an injury. A genetic study done in Mogil's lab a few years ago had indicated that microglia weren't as important in the pain circuit of female mice. So, the scientists decided to find out if interfering with the microglia would have the same effect in male and female mice.

Male mice had no pain, whereas female mice did

The researchers used mice that were suffering from a hypersensitivity to pain. The scientists gave them drugs that target the microglial cells in the spinal cord, in the hopes that this would prevent the animals from feeling pain. But only male mice responded to the drugs — the female mice still had an increased sensitivity to pain.

When the researchers repeated these experiments in mice under varying conditions, they saw the same results: male mice had no pain, whereas female mice did. "Whatever the manipulation is, in every case, blocking microglia or some part of the microglial system brings the pain sensitivity back to normal in male mice, and doesn't do anything in female mice," Mogil says.

In short, microglia don't seem to have anything to do with how female mice experience pain — even though the intensity of the pain is the same in both sexes. This means that there's another completely unknown biological culprit out there, Mogil says. "And it's actually more clinically relevant than the one we've been studying, given that the majority of chronic pain patients are women and that we know nothing about it at all."

"This is potentially a very important discovery which may go a long way to explain the marked differences in pain sensitivity and chronicity between women and men," says James McRoberts, a pain researcher at the University of California-Los Angeles who didn't take part in the study. McRoberts wants to see the study extended into other animals, such as rats, dogs, monkeys, and eventually humans — since, of course, mice are imperfect models.

"What is most striking is the magnitude of the differences."

"What is most striking is the magnitude of the differences — they really are all-or-none," says Michael Caterina, a neuroscientist at Johns Hopkins University who also didn't participate in the study. Yet, when one looks at the presence of the microglia in the spinal cord after injury, "the anatomy doesn’t give anything away." The work will probably provoke some significant discussion in the pain field, but also in neuroscience in general, he says.

So what exactly do female mice use instead of microglia? Mogil and his team suspect that a different kind of immune cell, called a T cell, may be involved instead. To test this idea, the researchers removed T cells from female mice. They found that under those conditions, female mice adapt and use the male microglial pain system. But when the researchers gave them their T cells back, the female mice stopped using the microglia. Still, exactly how T cells are involved in the pain experienced by female mice is anybody's guess.

Now that the researchers have identified this circuit, they will have to spend a lot more time figuring out how it works in female mice. Of course, eventually research on humans will have to take place as well. "The default assumption of all of biomedical research is that the biology in mice and rats is similar to the biology in humans until proven otherwise," Mogil says. But until human studies are carried out, that's just speculation.

While no pain medications on the market target microglia, basic science — like what Mogil is doing in mice — is what leads to new medicine. Male animals in general are used more often than female animals in medical research, despite the fact that men and women react differently to some drugs and are at risk for different diseases. This practice has a lot to do with the idea that hormonal changes in female mice introduce too much variability in results. Yet a number of studies including one from Mogil's lab — have shown that this isn't the case.

The NIH wants scientists to study more female animals and tissues

"In fact, if the people that had researched microglia 15 years ago had been using male and female mice, they would have noticed the difference right off the bat," Mogil says. But researchers "spent all their time and all their efforts studying male rodents, exclusively." And as Mogil’s study today shows, that limits our knowledge in a very real way.

To change this male-centered practice, the National Institutes of Health decided to impose new rules last year that would force biomedical researchers to counterbalance their use of male animals and biological tissues with the equivalent in female tissues and test subjects. The changes began rolling out in phases in October of last year.

As researchers start using more female mice, scientists may find more differences of this nature. Still, Mogil says that he didn't expect to find such a drastic distinction between males and females. "Here's a whole cell that is involved in this biological circuit in males and a completely different cell that's involved in the biological circuit in females," he exclaims. "I could be wrong, but I don't know that anyone ever found that before — outside of reproduction, of course."