Treating female pain may require a different approach than pain management for men. (My Ocean Production/Shutterstock)
Common treatments may not be as effective for women as they are for men, mouse model reveals
In a nutshell
- Research reveals that men and women experience pain through different biological pathways. In males, microglia cells activate pain through the protein Panx1, while in females, CD8+ T cells are responsible for triggering pain via Panx1.
- Understanding these biological differences opens the door for sex-specific pain treatments. For example, VEGF blockers could help men, while leptin inhibitors might be more effective for women, particularly in conditions like fibromyalgia.
- The study highlights the need for pain research to include both sexes to develop more effective treatments. Women, who are disproportionately affected by chronic pain, may benefit from therapies tailored to their unique biological processes.
CALGARY, Canada — For decades, women suffering from chronic pain have been told “it’s all in your head” when treatments that work for men fail them. Now, research from the University of Calgary reveals that women’s pain actually operates through entirely different biological pathways than men’s. Scientists have discovered that the same protein triggers pain in both sexes, but through completely different immune cells and chemical signals.
A new study published in Neuron reveals that a protein called pannexin-1 (or Panx1 for short) works differently in males and females. This helps to explain why women are more likely to develop chronic pain conditions and why they often don’t respond as well to certain treatments.
The Divide in Pain Research
Most pain research has historically focused on male subjects, even though women make up the majority of chronic pain patients. This study aims to fix that imbalance by looking at both male and female animals to understand why pain works differently between sexes.
While both sexes use the Panx1 protein in their immune cells to create pain signals, they use completely different cells and chemical messengers to do it.
In males, Panx1 works through cells called microglia (the immune cells of the spinal cord and brain) to release a protein called VEGF, which increases pain sensitivity. In females, however, Panx1 works through CD8+ T cells (a type of white blood cell) to release leptin, a hormone best known for its role in hunger and metabolism. This may help explain why treatments that target microglia cells work well for reducing pain in males but often fail in females.
Crossing Biological Boundaries
When they took microglia cells from male animals, activated them, and transferred them into females, the females developed pain. Similarly, when they transferred activated female T cells into males, the males also developed pain. This confirmed that these sex-specific mechanisms weren’t just correlations; they actually cause pain.
The researchers also created mice that lacked the Panx1 protein specifically in microglia cells. Male mice without this protein showed much less pain after nerve injury, while female mice still developed normal pain sensitivity.
When they analyzed fluid from the spinal cord, they found that after nerve injury, males had higher levels of VEGF while females had higher levels of leptin. Blocking VEGF reduced pain in males but not females, while neutralizing leptin reduced pain in females but not males.
Hope for Better Pain Treatments
This could lead to better pain treatments for everyone. Current treatments for neuropathic pain (pain caused by nerve damage) include anticonvulsants, antidepressants, and opioids. These treatments tend to work less effectively in women and often cause worse side effects.
With this new knowledge, doctors might eventually be able to prescribe treatments targeted specifically to each sex, like VEGF blockers for men and leptin blockers for women.
This discovery is particularly important for conditions like fibromyalgia, which affects women much more often than men. Previous studies have shown that leptin levels can predict pain severity in women with fibromyalgia. This research now provides a possible explanation for that connection.
Panx1 could be a treatment target that works for both sexes. Although the way the body reacts to this protein is different for men and women, medications targeting it could help both, potentially transforming pain treatment.
For women who have struggled to have their pain taken seriously or effectively treated, this research provides solid evidence that treating female pain really may deserve specific research and targeted treatments. Doctors may eventually move beyond one-size-fits-all approaches to develop treatments tailored to each person’s unique biology.
Paper Summary
Methodology
The researchers induced nerve injury in both male and female rats and mice by cutting specific branches of the sciatic nerve. They measured pain sensitivity using a test that assesses how much pressure an animal can tolerate before withdrawing its paw. To investigate cellular mechanisms, they isolated specific immune cells from spinal cord tissue and measured Panx1 activity. They also created mice with targeted genetic deletion of Panx1 in specific cell types and performed transfer experiments, where they activated specific immune cells and injected them into the spinal cord of uninjured animals to see if they could trigger pain.
Results
In male rodents, nerve injury increased Panx1 expression specifically in spinal microglia, and blocking Panx1 significantly reduced pain. Removing Panx1 genetically from microglia prevented pain development in males but had no effect in females. Analysis of spinal fluid showed that nerve injury increased VEGF-A levels in males and leptin levels in females. Blocking the VEGF receptor reversed pain in male but not female rodents, while neutralizing leptin reversed pain in female but not male rodents. When activated male microglia were transferred into either male or female recipients, they induced pain that was blocked by inhibiting VEGF-A. Similarly, female-derived CD8+ T cells released leptin through Panx1 activation, and transferring these cells caused pain that was prevented by neutralizing leptin.
Limitations
The researchers acknowledge that animal models may not perfectly translate to humans. The study focused primarily on pain sensitivity to touch but didn’t extensively investigate other pain types important in clinical settings. The research examined mostly short-term interventions rather than long-term treatments. While the researchers attribute the observed effects to specific immune cells, they cannot exclude the potential involvement of other cell types. They also found that some inflammatory proteins were elevated in both sexes after nerve injury, suggesting additional shared mechanisms may contribute to pain alongside the sex-specific pathways identified.
Discussion and Takeaways
This study provides a biological explanation for why women are overrepresented in chronic pain conditions and often respond differently to pain medications. It suggests that the immune system’s role in pain is fundamentally different between sexes, with males relying more on innate immune responses (microglia) and females more on adaptive immune responses (T cells). The findings validate including both sexes in pain research and offer potential new treatment targets. For conditions like fibromyalgia that predominantly affect women, targeting the leptin pathway specifically might provide more effective relief. Meanwhile, the identification of Panx1 as a common molecular target across sexes suggests that drugs targeting this channel might benefit both men and women with neuropathic pain.
Funding and Disclosures
The research was primarily supported by grants from the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada. Additional funding came from the Hotchkiss Brain Institute and the Louise and Alan Edwards Foundation. Two researchers reported potential conflicts of interest: Dr. Trang is cofounder and CEO of AphioTx Inc., and Dr. Zamponi is cofounder and CSO of Zymedyne Therapeutics. Both hold patents for pain-related therapies, though they note these patents don’t pertain to the current findings.
Publication Information
The study titled “Divergent sex-specific pannexin-1 mechanisms in microglia and T cells underlie neuropathic pain” was published in the March 19, 2025, issue of the journal Neuron (Volume 113, pp. 896-911). The research was conducted at the University of Calgary in Canada, with contributions from McGill University and other institutions.
