Summary: Scientists have discovered that female hormones like estrogen and progesterone can trigger immune cells near the spinal cord to release natural opioids, easing pain before it reaches the brain. These immune cells, known as T regulatory cells (T-regs), are located in the meninges and produce the painkilling molecule enkephalin in response to hormonal signals.
The effect appears specific to females, offering insight into why some pain treatments work better for women and why postmenopausal women may experience more chronic pain. This newly uncovered mechanism could lead to sex-specific therapies and innovative treatments for the millions affected by chronic pain.
Key Facts:
- Hormone-Driven Relief: Estrogen and progesterone prompt T-regs to release natural opioids.
- Sex-Specific Response: Female mice without T-regs became more pain-sensitive; males did not.
- Therapeutic Potential: Engineered T-regs may offer a new approach for chronic pain relief.
Source: UCSF
Scientists have discovered a new mechanism that acts via an immune cell and points toward a different way of treating chronic pain.
Female hormones can suppress pain by making immune cells near the spinal cord produce opioids, a new study from researchers at UC San Francisco has found. This stops pain signals before they get to the brain.
The discovery could help with developing new treatments for chronic pain. It may also explain why some painkillers work better for women than men and why postmenopausal women experience more pain.
The work reveals an entirely new role for T regulatory immune cells (T-regs), which are known for their ability to reduce inflammation.
“The fact that there’s a sex-dependent influence on these cells – driven by estrogen and progesterone – and that it’s not related at all to any immune function is very unusual,” said Elora Midavaine, PhD, a postdoctoral fellow. She is the first author of the study, which was funded in part by the National Institutes of Health.
It appears April 4 in Science.
The researchers looked at T-regs in the protective layers that encase the brain and spinal cord in mice. Until now, scientists thought these tissues, called the meninges, only served to protect the central nervous system and eliminate waste. T-regs were only discovered there in recent years.
“What we are showing now is that the immune system actually uses the meninges to communicate with distant neurons that detect sensation on the skin,” said Sakeen Kashem, MD, PhD, an assistant professor of dermatology.
“This is something we hadn’t known before.”
That communication begins when a neuron, often near the skin, senses something that could cause pain. The neuron then sends a signal to the spinal cord.
The team found that the meninges surrounding the lower part of the spinal cord harbor an abundance of T-regs. To learn what their function was, the researchers knocked the cells out with a toxin.
The effect was striking: Without the T-regs, female mice became more sensitive to pain, while male mice did not. This sex-specific difference suggested that female mice rely more on T-regs to manage pain.
“It was both fascinating and puzzling,” said Kashem, who co-led the study with Allan Basbaum, PhD. “It actually made me skeptical initially.”
Further experiments revealed a relationship between T-regs and female hormones that no one had seen before: Estrogen and progesterone were prompting the cells to churn out painkilling enkephalin.
Exactly how the hormones do this is a question the team hopes to answer in a future study. But even without that understanding, the awareness of this sex-dependent pathway is likely to lead to much-needed new approaches for treating pain.
In the short run, it may help physicians choose medications that could be more effective for a patient, depending on their sex. Certain migraine treatments, for example, are known to work better on women than men.
This could be particularly helpful for women who have gone through menopause and no longer produce estrogen and progesterone, many of whom experience chronic pain.
The researchers have begun looking into the possibility of engineering T-regs to produce enkephalin on a constant basis in both men and women.
“If that approach is successful, it could really change the lives of the nearly 20% of Americans who experience chronic pain that is not adequately treated,” Basbaum said.
Authors: Other authors on the study include Beatriz Moraes, Jorge Benitez, Sian Rodriguez, Joao Braz, Nathan Kochhar and Walter Eckalbar of UCSF, Lin Tian of the Max Planck Florida Institute for Neuroscience, Ana Domingos of University of Oxford and John E. Pintar of Rutgers Robert Wood Johnson Medical School.
Funding: This study is funded in part by National Institutes of Health grants (T32AR007175-44, NSR35NS097306). For other funders, please see the study.
About this pain research news
Author: Robin Marks
Source: UCSF
Contact: Robin Marks – UCSF
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Meningeal regulatory T cells inhibit nociception in female mice” by Elora Midavaine et al. Science
Abstract
Meningeal regulatory T cells inhibit nociception in female mice
T cells have emerged as orchestrators of pain amplification, but the mechanism by which T cells control pain processing is unresolved.
We found that regulatory T cells (Treg cells) could inhibit nociception through a mechanism that was not dependent on their ability to regulate immune activation and tissue repair.
Site-specific depletion or expansion of meningeal Treg cells (mTreg cells) in mice led to female-specific and sex hormone–dependent modulation of mechanical sensitivity.
Specifically, mTreg cells produced the endogenous opioid enkephalin that exerted an antinociceptive action through the delta opioid receptor expressed by MrgprD+ sensory neurons.
Although enkephalin restrains nociceptive processing, it was dispensable for Treg cell–mediated immunosuppression.
Thus, our findings uncovered a sexually dimorphic immunological circuit that restrains nociception, establishing Treg cells as sentinels of pain homeostasis.
