Girls Take Longer to Resolve Ache Than Males. Researchers Might Lastly Know Why.

Sex differences in anti-inflammatory signaling may explain why women often experience more severe and persistent pain, a mouse study suggests.

Women often report more severe and long-lasting pain than men, and findings from a new study in mice suggest that the experience is not merely subjective.

Neuroimmunologist Geoffroy Laumet at Michigan State University and his colleagues recently discovered that anti-inflammatory signaling was less active in female mice than in their male counterparts, and this was likely due to sex hormone differences.¹ As a result, male mice managed to resolve inflammation and pain sooner. The findings, published in Science Immunology, may someday help women get more appropriate treatment for their pain.

“The difference in pain between men and women has a biological basis,” Laumet said in a statement. “It’s not in your head, and you’re not soft. It’s in your immune system.”

Immune responses, which are closely tied to pain, are also known to differ between males and females.^2-5 Laumet wondered if this could explain the differences in pain experience between the two sexes.

In the study, Laumet’s team hypothesized that the anti-inflammatory cytokine interleukin 10 (IL-10), which the researchers previously found to modulate pain in mice, may contribute to this effect.^6-8 To test this hypothesis, the team genetically engineered mice to produce fluorescent IL-10 so that they could detect immune cells expressing the molecule using flow cytometry. They induced inflammation and pain by injecting a potent immune system activator called complete Freund’s adjuvant (CFA), which contains heat-inactivated bacteria and paraffin, into the mice’s skin.

Seven days after CFA injection, male mice began showing signs of pain resolution. These mice also showed a significant increase in IL-10-positive cells in their paw skin relative to their counterparts that received saline. The paw skin of female mice, which did not start to resolve their pain until at least day 10, had fewer IL-10-positive immune cells, indicating that IL-10 could indeed underlie the sex differences in pain perception.

Next, the researchers investigated the effects of an experimental sex change on IL-10 production and pain resolution. To induce male-like phenotypes in female mice, the team removed the mice’s ovaries, and then they implanted pellets of dihydrotestosterone (DHT), a potent derivative of testosterone, which allowed continuous release of the hormone. These mice had higher IL-10 levels and began to resolve pain days sooner than their female counterparts that either had a sham surgery or had their ovaries removed but received placebo. Similarly, when researchers induced female-like phenotypes in male mice by removing their testicles, the mice had lower IL-10 levels and resolved pain slower than their counterparts that underwent sham surgery.

Finally, to test the relevance of their findings in humans, Laumet’s team analyzed existing data from thousands of patients with traumatic injury. The analysis revealed that women reported prolonged and more severe pain than men up to several months following their injury. This difference correlated with significantly lower IL-10 levels, further supporting the researchers’ hypothesis on the anti-inflammatory molecule’s role in mediating sex differences in pain.

Laumet hopes that his team’s findings may someday be clinically translated. He envisions “new avenues for non-opioid therapies aimed at preventing chronic pain before it’s established.”