Men and Women, Male and Female Animals: What’s the Deal with Sex Differences in Chronic Pain? (Part 1)

Sex differences in chronic pain

Researchers are identifying the biological basis for differences between the sexes when it comes to the development of chronic pain, both in people and in rodents. The payoff for a better understanding could one day be huge for patients. Image credit: Iurii Golub/123RF Stock Photo.

Editor’s note: This is part one of a two-part RELIEF feature article. See part two here.

Do men and women experience pain differently? That question has been the subject of decades of research, but today scientists are investigating it in a whole new way. Rather than simply measuring quantitative differences in people—who has more pain—researchers are now finding differences everywhere they look by studying the basic biology underlying pain in male and female animals.

The results have far-reaching and surprising implications. Although, by and large, males and females seem to experience pain in roughly the same ways, there may be fundamentally different biological underpinnings that lead to pain. Immune cells and hormones play crucial roles, but how they wield influence in each sex remains unclear. Males and females also differ biologically in how they respond to pain-relieving opioid drugs, and even how their bodies produce naturally occurring opioids, known as endogenous opioids.

A better picture of the biological processes that result in chronic pain in males and in females could allow researchers to more successfully target those processes using new drugs. Such treatments might be entirely different for men and for women.

Sex or gender?
Women are affected by chronic pain conditions in far greater numbers than men. But is that a difference of biology, or are gender differences responsible? (While sex is determined biologically, gender is a social construct that applies to people but not animals.)

Women do seek out both health care and pain care at higher rates than men. And one study found that women rated their pain higher than men with the same painful conditions.

“Clearly there are gender differences in pain,” said Jeffrey Mogil, a researcher at McGill University in Montreal, Canada, who studies sex differences in pain. “They involve potential differences in reporting; women report more pain. Who’s doing it accurately?”

The issue is complicated by the societal expectations that men should “be tough,” perhaps keeping their pain (and emotions in general) to themselves, whereas emotional expression by women is more socially accepted. On the other hand, historically, women have often been dismissed as overly emotional—think “hysterical”—when they report pain or other symptoms, particularly those symptoms that can’t be medically explained. “Are women complaining and reporting too much, or are men complaining too little?” Mogil asked.

Researchers tried to resolve the question of whether men or women were more sensitive to pain in the laboratory by measuring the pain threshold (the lowest stimulus intensity that an individual says is painful), tolerance (the level or duration of pain that a person can handle), and pain ratings (how much pain a person reports). Many of those studies have been inconclusive, but when researchers have found differences between the sexes, they overwhelmingly indicate that women are more sensitive to pain than are men, Mogil said. How much more sensitive is up for debate, and requires a value judgement, Mogil added.

But while the findings seem to indicate a sex difference, gender differences might be at play even in the controlled laboratory setting. That’s because in lab studies people report their pain, and a pain report is just that: a verbal, subjective report of a number to represent a person’s pain on a scale of “no pain” to “worst imaginable pain.” Considering that women typically suffer from menstrual pain starting in adolescence, and many experience childbirth, their ratings may differ from men’s.

“If women have more experience with pain than men, they might be better able to picture what maximal pain possible is,” Mogil said, and they might be more accurate in their pain assessment.

The responses of people who participate in research studies can also be influenced by their own gender expectations. For example, men might report less pain because they feel they have to “act macho.”

“Some have argued that once you factor all those things out, there are no sex differences at all” in pain sensitivity, Mogil said

Far more interesting, Mogil explained, is how pain arises in the sexes.

“Men and women either feel pain to the same degree, or they don’t. In any case, do they do it using the same biological circuitry? And research is increasingly showing that pain processing is different in males and females,” despite reporting similar feelings of pain, according to Mogil.

To get at those biological underpinnings of pain, Mogil has been studying pain in male and female animals for over twenty years. For most of that time, he was one of very few researchers doing so, but lately other scientists are rapidly joining in. Clinical trials of new drugs in all areas of medicine were conducted almost exclusively in men until the 1990s, when the US Food and Drug Administration (FDA) recognized that medications tested solely in men might not be safe or effective for women. Just since 2014, the National Institutes of Health (NIH), the major research-funding agency in the US, has taken the step of requiring researchers to plan to use male and female animals in so-called preclinical research (see related IASP Pain Research Forum news).

Looking to immune cells to explain sex differences in pain
In a striking 2015 study, Robert Sorge, then a postdoctoral researcher working in Mogil’s laboratory and now an independent investigator at the University of Alabama at Birmingham, found that male and female mice developed chronic pain in entirely different ways, despite displaying similar pain behaviors.

Research from several labs had suggested that microglia, immune cells that reside inside the brain and spinal cord, played a key role in the progression to chronic pain in mice. But that research had been undertaken using male animals. So Mogil and Sorge examined both male and female mice, using mouse models of neuropathic (nerve injury) and inflammatory pain. The researchers treated the animals with drugs to inhibit the activity of microglia in the spinal cord. They found that the drugs eased pain sensitivity in male mice—but had no such effect in females.

Instead, chronic pain in females seemed to depend not on microglia in the spinal cord but on a different type of immune cell, called T cells. When the researchers depleted the female mice of T cells, they became sensitive to the microglia inhibitors. This indicated that the animals had “switched” from one biological pathway to another, depending on what cells were available.

That’s not so surprising, Mogil says.

“At the end of the day, we find a lot of switching examples in biology; there are multiple routes to get to the same end. There is a lot of redundancy.”

Since the early pioneering work from Mogil, dozens of studies over the past several years have uncovered an array of biological differences in male vs. female animals.

“We see quite profound sex differences in the mechanisms that seem to be driving chronic pain,” said Ted Price, a pain researcher at the University of Texas at Dallas. Immune cells seem to be a recurring theme.

“Essentially, our findings have been a perfect parallel to Dr. Mogil’s findings,” Price said. “It seems that there’s a really strong microglia component in males—and maybe macrophages as well, which are a type of blood cell—and we just don’t really see that in females.” In any case, he said, “the neuro-immune interactions seem to be very different in males and females,” referring to connections between the nervous system and the immune system.

Are sex differences in pain limited to the immune system?

“They’re definitely not,” said Price. For example, he and others have found cognitive deficits accompanying chronic pain in males that don’t seem to affect females the same way.

“There is a huge difference in the impact of neuropathic pain on the prefrontal cortex in males versus females that we really just don’t understand,” Price said, referring to a region at the front of the brain known to be involved with complex cognitive processes.

Hormones, pain and sex differences: a complex picture
When it comes to a role for hormones in sex differences in pain, researchers say their understanding is murky at best. The role of estrogen, in particular, has vexed scientists—does it worsen pain, or alleviate it? And while estrogen has been the hormone of focus in pain research, other hormones may be just as influential.

“For us, the hormone in question has been testosterone,” Mogil said. “It’s equally as capable of producing differences as estrogen is.” Indeed, he found that testosterone did play a critical role in the contribution of microglia to pain in male mice.

Some clues about the role of hormones have come from patients.

“It is pretty well known that migraine is two to three times more common in women,” said Greg Dussor, who studies migraine at the University of Texas at Dallas (see related RELIEF interview with Dussor). “The prevalence in men and women is pretty similar before the start of menstruation and after menopause.”

But during the time in between, migraine becomes more common in women, and more severe for women who already have it. “The number of attacks in a cycle becomes more frequent, and they drop off after menopause. That strongly implicates hormones, but that’s an umbrella term,” Dussor said. “We don’t know which hormones are acting, or where. It’s confusing.”

Dussor continued, “It is looking like testosterone is protective against chronic pain in people as well as animals. So it’s not just factors in females that make them more susceptible; there are protective factors in males.”

Whether someone develops chronic pain, or how severe it is, might depend on a complex balance of multiple hormones, Dussor said, even beyond testosterone and estrogen.

Jessica Ross, a postdoctoral pain researcher studying sex differences in pain at Stanford University, said the impacts of hormones are even more complex because they’re ever changing.

“The most important takeaway for hormonal influences is that you need to study them across the lifespan,” she said.

Some changes begin at the earliest stages of development, whereas others are triggered later, during puberty. “It’s important to know where the differences are coming from,” according to Ross.

A role for peptides
The influences of sex hormones might be so muddled because they’re not always direct influences. Hormones are by definition chemical signals that travel through the bloodstream to produce changes at many cell types and organs throughout the body. That includes influencing other hormones as well as signaling molecules made of tiny proteins called peptides. Whereas male pain signaling seems to rely heavily on immune cells, female chronic pain may depend more on peptides, Price said.

One such peptide is called calcitonin gene-related peptide, or CGRP. Dussor was looking into the hypothesis, as were many other groups, that CGRP contributes to migraine. At the same time, Dussor said, “there was a parallel hypothesis about neurons in the meninges” playing a role in migraine, “so we thought maybe CGRP was working there.” (The meninges are the membranes that surround the brain and spinal cord.)

But a 2005 study in male rodents showed that CGRP applied to neurons of the meninges didn’t change how the neurons functioned, as would have been expected if CGRP triggered headache pain by affecting those neurons.

“That was kind of a problem for the hypothesis and was really the origin of why we started this line of research,” Dussor said. “We thought, Maybe there’s something we’re missing—let’s try a behavioral experiment.”

So Dussor and his team applied CGRP to the meninges of male rats and looked for signs that suggested the animals were having something resembling a headache.

“We found the data were exactly consistent with that prior 2005 study,” he said, meaning CGRP had no effect in males. But when they applied CGRP to the meninges of female rats, “that’s when we saw a robust response that just wasn’t there in the males, and that ignited the whole story.”

CGRP is not a traditional immune system component or a hormone, Dussor said, “so it’s surprising—it’s off the list of what you’d expect to be different in males and females, and yet here it is.” (CGRP is the target of a whole new class of drugs recently approved for migraine; see related RELIEF feature article).

See part two of this feature article here, which discusses the role of sex differences in the response to opioid drugs as well as in the workings of the body’s own opioids.

Stephani Sutherland, PhD, is a neuroscientist and freelance journalist in Southern California. Follow her on Twitter @SutherlandPhD