Chronic pain management may have a new angle, with a recent finding that regulatory T cells in female mice influence their pain perception.
By Helen Petre
Everyone hurts sometimes, and some people hurt all the time. Chronic pain affects one third of the population of the United States, according to the U.S. Department of Health and Human Services. They cite it as the primary reason Americans are on disability and unable to work, and the primary reason Americans see medical physicians. Recent research published in Science reports on the work of a research group that discovered a potential new method for pain management. There are many questions still to answer; however, there is a definite decrease in pain in female mice expressing enkephalin in response to mechanical stimulation of meningeal regulatory T cells.
Scientists at the University of California, San Francisco, have discovered that immune cells modulate chronic pain. This is new. We thought immune cells modulated inflammation, or fought off cancer or virus infections, but who knew that immune cells could talk to neurons and tell them not to tell the brain that it hurts? Pain perception and processing is different in males and females. We do not know how that happens, or why, and it is difficult to quantify pain. Dr. Midavaine and her lab team figured out a way to do this and determined that female hormones, estrogen and progesterone, regulate immune cells in the meninges surrounding the lumbar and sacral regions of the spinal cord of mice. When the skin over the lower back is mechanically stimulated, regulatory T cells produce enkephalin, a protein that binds to opioid binding sites on sensory neurons, but only in females, with estrogen and progesterone. The sensory neurons don’t fire, and this effectively suppresses pain signals from getting to the brain.
This discovery could lead to better management of chronic pain. It also explains why men and women respond to pain medications differently, and why postmenopausal women experience significantly more pain. There is much to understand.
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Immune cells
There are many different types of immune cells, and they all have different jobs. Some kill cells that are not part of the body, or have cancer. Some produce antibodies in response to bacteria, viruses, or allergens. Some just respond to any sort of unusual thing, like a cut or bruise. The immune cells studied here are regulatory T cells that are a subset of CD4, or helper T cells. Regulatory T cells regulate other immune cells. They tell other immune cells what to do. Sometimes they encourage immune responses like inflammation. Sometimes they reduce inflammation. It all depends on the circumstances.
Sometimes it is good to have an immune response. Say for example, you break your leg. It hurts, gets swollen, turns red, and makes you want to not move it or walk around on it. That is a good thing. All that swelling and extra blood flow makes all the tissues press on each other, and that makes them all hurt more, so maybe it is a good idea to put some ice on it and prevent it from swelling too much. Ice reduces swelling; regulatory T cells do, too. They modulate the response. The researchers who published this article, however, found and described a new function for regulatory T cells. They found that regulatory T cells actually modulate neurons, by producing opioids that bind to opioid receptor sites on sensory neurons, preventing the neurons from firing and preventing the pain signal from getting to the brain.
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How does your brain know you are in pain?
When something mechanical happens to your body, like you drop a brick on your toe, the cells in your toe get squeezed, broken, and ripped apart. There are many nociceptors, or pain sensors, in your skin that notice this injury and send this information to the brain. They tell the brain that something bad happened, the toe is squished, or maybe the bone is broken, or the skin is torn, and they also tell the brain where in the body this painful mechanical stimulus occurred.
There are separate sensors in the skin for pain, itch, tickle, hot, cold, and even light and deep touch. The researchers found that only after mechanical stimuli, and somehow only in female mice with estrogen, the regulatory T cells modulate the response by producing opioids that bind to binding sites on sensory neurons, preventing the brain from getting the pain signals. That is such an unusual and unexpected finding that one of the researchers, Dr. Kashem, said he was skeptical at first. When I read the article I was skeptical too. It sounds amazing. There are also many, many unanswered questions about how and why this happens. The results show it happened only with mechanical stimulation. Why just mechanical stimulation? How does this work, and how did they figure this out?
The discovery
The research team chose to work with meningeal regulatory T cells because they found many of these cells in the meninges surrounding the lower spinal cord of mice. Meninges are protective layers that surround the brain and spinal cord. Dr. Midavaine was surprised to find T cells in the meninges. I was too. Meninges are layers of connective tissue that contain cerebrospinal fluid. The fluid is derived from blood, but has no blood cells, just clear plasma, nutrients, and, well, T cells? Dr. Midavaine reported that this is highly unusual.
Figure 1 shows the production of cerebrospinal fluid in the choroid plexuses in the ventricles of the brain in a cross section. Cerebrospinal fluid is continually being made and drained through the arachnoid granulations back into the blood. The fluid is always clean and full of nutrients. It contains no red blood cells and fewer than five white blood cells per cubic millimeter. In contrast, blood has between 5,000 and 10,000 white blood cells per cubic millimeter. T cells are lymphocytes, a type of white blood cell.
The results
The research team carried out many complex experiments to determine what was actually happening: They destroyed the T cells. They increased the cells in both males and females. Then they tried different ways to make the mice experience pain, and recorded results. There was no difference in response to hot or cold or any other stimuli except mechanical stimulation. There was no difference in response to mechanical stimulation in male mice with T cells or without T cells. Only females expressed low response to mechanical stimulation with higher levels of T cells.
There were striking differences between male and female responses to mechanical stimulation. When they deleted the regulatory T cells, female mice became more sensitive to pain, while male mice did not. When they increased the regulatory T cells, female mice became less sensitive to pain, while male mice did not.
T cell sensory neuron interactions
Now that the research team had a significant difference, they tried to learn why. The sensory neurons of female mice were simply not firing as much when the T cells were at high levels. Why?
Sensory neurons receive information about things that you can sense, like pain, pressure, and temperature. Then they bring the information to the central nervous system for processing. The researchers found that meningeal regulatory T cells secreted enkephalin when presented with a painful mechanical stimulus, but only in the presence of estrogen and progesterone. Enkephalin binds to opioid receptors on sensory neurons, which decreases sensitivity of the neurons by reducing calcium activity. The sensory neurons do not transfer the pain message to the brain. If the brain does not know there is pain, then there is no pain, even if there is reason for pain.
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Estrogen and progesterone
Why is the difference so striking between sexes? Hormones of course. Estrogen and progesterone prompt the regulatory T cells to secrete the enkephalin. Exactly how this happens, no one knows. This is a sex dependent response that relies on the presence of female sex hormones.
Conclusion for chronic pain
This new found knowledge is astonishing and provides hope for men and women experiencing chronic pain. Further research is necessary to perhaps engineer regulatory T cells, or enkephalins, and find out how and where they can be used to reduce the perception of pain and suppress sensory neurons, maybe without female hormones. There is much to learn about how this pain regulation system works and much promise and hope for people in chronic pain.
Why do regulatory T cells produce enkephalins only in women, only in the presence of estrogen? No one knows. This means that premenopausal women experience less pain than postmenopausal women, or well, actually not women, mice. If scientists can understand how this works, and if they conclude it works the same way in humans as in mice, then they may be able to make drugs, like enkephalins, and provide them to postmenopausal women and men, and in theory, the drugs should reduce pain. If it is possible to engineer a mechanism similar to the wild type system described in female mice here, and if it can work in humans without the hormones, it would be life changing for anyone with chronic pain.
This study was published in the peer-reviewed journal Science.
References
Midavaine, E., Moraes, B. C., Benitez, J., Rodriguez, S. R., Braz, J. M., Kochhar, N. P., Eckalbar, W. L., Tian, L., Domingos, A. I., Pintar, J. E., Basbaum, A. I., & Kashem, S. W. 2025. Meningeal regulatory T cells inhibit nociception in female mice. Science, 388(6742), 96–104. https://doi.org/10.1126/science.adq6531
U.S. Department of Health and Human Services. (2020, November 5). Opioids – Digital Media Kit. National Institutes of Health. https://www.nih.gov/news-events/opioids-digital-press-kit
Wikipedia. (2025, May 25). Cerebrospinal fluid. https://en.wikipedia.org/wiki/Cerebrospinal_fluid
About the Author
Helen Petre is a retired biologist. She spends her time with her grandchildren and volunteering with science related projects, striving to share the excitement of learning with future generations.
