Summary: It is a long-documented phenomenon that women experience chronic pain more frequently and for longer durations than men, but the reason why has often been dismissed as subjective. New research has uncovered a biological basis for this disparity: hormone-regulated immune cells called monocytes.
The study reveals that in males, high levels of testosterone activate these cells to release IL-10, a molecule that signals neurons to shut down pain. In females, these cells are less active, leading to delayed recovery and persistent pain. This discovery shifts the focus from how pain begins to why it stays, offering a potential path for non-opioid treatments that actively resolve pain.
Key Facts
- Active Pain Resolution: Pain relief is not a passive process; it is an active immune-driven mechanism powered by monocyte-derived IL-10.
- The Testosterone Trigger: Higher levels of male sex hormones, like testosterone, make monocytes more efficient at producing the “off-switch” for pain.
- Delayed Recovery in Females: Because female monocytes are less active, pain lasts longer, and the body takes more time to resolve the initial neural activation.
- Neural-Immune Pathway: Monocytes directly communicate with pain-sensing neurons to quiet them down.
- New Therapeutic Avenues: By targeting this specific pathway, researchers hope to develop non-opioid therapies that “boost” the immune system’s ability to turn off pain.
Source: Michigan State University
Chronic pain lasts longer for women than men, and new research suggests differences in hormone-regulated immune cells, called monocytes, may help explain why.
In a new paper in Science Immunology, researchers at Michigan State University found a subset of monocytes release a molecule to switch off pain. These cells are more active in males due to higher levels of sex hormones such as testosterone, the team found.
Females, however, experienced longer-lasting pain and delayed recovery, because their monocytes were less active. Geoffroy Laumet, MSU associate professor of physiology, and Jaewon Sim, a former graduate student in his lab, discovered the same pattern in both mouse models and human patients.
These findings, funded by the National Institutes of Health and the Department of Defense, could mean those immune cells can be manipulated into producing more signals to calm pain. While a new treatment is likely decades away, Laumet hopes this research could one day help millions of people experience relief with non-opioid treatments — and ensure women’s pain is taken seriously.
“The difference in pain between men and women has a biological basis,” Laumet said. “It’s not in your head, and you’re not soft. It’s in your immune system.”
Pain results when neurons found throughout your body are activated by stimulation. Most of the time they’re silent, but they become activated when you stub your toe or fall off a bike. But for those with chronic pain, the sensors may be activated with mild stimulation, or even no stimulation at all.
Doctors still rely on patients rating their pain on a scale of one to 10. The problem is everyone experiences pain differently. So, when more women than men complain of long-lasting or chronic pain, the difference is often chocked up to perception or reporting.
Laumet has devoted his lab to studying pain for six years. His team was researching a small pilot project when they noticed higher levels of interleukin-10, or IL-10, in males. When the second test again showed higher levels of the substance that signals to neurons to shut down pain, they realized they were onto something.
“That was the turning point for me,” Sim said. “I feel extremely fortunate that we trusted those early, uncertain findings and chose to pursue them further.”
Laumet’s lab dove into the research using a sophisticated technique called high-dimensional spectral flow cytometry. They learned that monocytes, long thought to be precursor cells without much of a function, play an essential and direct role in communicating with pain-sensing neurons by producing IL-10.
Laumet’s team found that IL-10-producing-monocytes were much more active in males than females. When they blocked male sex hormones, they received the opposite result.
“This study shows that pain resolution is not a passive process,” Laumet said. “It is an active, immune-driven one.”
Laumet’s team performed at least five types of tests on mouse models to make sure what they saw wasn’t an anomaly. Each time, the results were the same.
That’s when he reached out to Sarah Linnsteadt, a colleague at University of North Carolina at Chapel Hill who was studying the psychological outcomes of people in car accidents. Her research showed a similar pattern — men had more active IL-10-producing-monocytes and resolved pain faster.
This new evidence illuminates the immune–neural pain resolution pathway, shifting the thinking from how pain starts to why pain persists. The next step is to investigate how treatments could target this pathway and boost IL-10 production. These treatments could help pain resolve faster instead of just blocking pain signals.
“Future researchers can build on this work,” Laumet said. “This opens new avenues for non-opioid therapies aimed at preventing chronic pain before it’s established.”
Key Questions Answered:
A: This study proves the difference is biological, not just perceptual. It’s in the immune system. Because of how hormones interact with immune cells, the actual mechanism for “turning off” pain is slower in females.
A: While testosterone does trigger the monocytes, the goal isn’t necessarily hormone therapy. Now that we know the monocytes are the “workers,” the next step is finding a way to trigger them directly or mimic the IL-10 signal they produce, regardless of a person’s hormone levels.
A: Most pain meds just block the signal. This research looks at how to end the pain by helping the body resolve it naturally. It opens the door for non-opioid treatments that actually help the body finish the job of healing.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this pain and neuroscience research news
Author: Bethany Mauger
Source: Michigan State University
Contact: Bethany Mauger – Michigan State University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Monocyte-derived IL-10 drives sex differences in pain duration” by Jaewon Sim, Elizabeth O’Guin, Chiho Sugimoto, Sophie Laumet, Karli Monahan, Matthew P. Bernard, Samuel A. McLean, Liz M. Albertorio-Sáez, Ying Zhao, Hariharan Ramakrishnan, Sabrina de Souza, Olivia C. Eller, Christine J. Smoyer, Kyle M. Baumbauer, Matthias Mack, Joseph K. Folger, Alfred J. Robison, Sarah D. Linnstaedt, and Geoffroy Laumet. Science Immunology
DOI:10.1126/sciimmunol.adx0292
Abstract
Monocyte-derived IL-10 drives sex differences in pain duration
Women frequently experience longer-lasting pain than men, indicating delayed pain resolution, but the mechanisms underlying this sex difference remain unclear. Here, we show that interleukin-10+ (IL-10+) monocytes resolve inflammatory pain by signaling to IL-10R1+ sensory neurons in a mouse model of skin inflammation.
Male mice exhibited faster pain resolution than females, which was associated with higher numbers of IL-10+ monocytes. In both sexes, pain resolution was impaired by deleting Il10 from monocytes or Il10ra from sensory neurons.
Androgen signaling promoted IL-10 production by monocytes, driving sex differences in IL-10+ monocyte abundance. Enhancing IL-10+ monocytes with resolvin D1 accelerated pain resolution in both sexes.
In humans, pain resolved faster in men than in women after traumatic injury and was associated with higher circulating monocytes and IL-10 levels in men.
These findings identify a role for peripheral IL-10+ monocytes in sex-specific pain resolution and highlight immune mechanisms that may prevent chronic pain.
