Female Hormones Activate Secret Defense Against Pain

Scientists have discovered that immune cells called Tregs, located in the meninges (the layers that protect the brain and spinal cord), help control pain in females by producing a natural substance called enkephalin, which blocks pain signals before they reach the brain. This effect depends on the female hormones estrogen and progesterone. The discovery could explain differences in pain between men and women and pave the way for new treatments for chronic pain.

Chronic pain affects millions of people around the world and is still difficult to treat. Now, a study from the University of California, San Francisco (UCSF) has made a surprising discovery: immune cells located in the layers that protect the brain and spinal cord, called the meninges, help control pain.

What’s most striking is that this mechanism appears to be different between men and women, influenced by the female hormones estrogen and progesterone. This new understanding could pave the way for more personalized and effective treatments for pain.

Scientists focused on a specific type of immune cell called regulatory T cells, or Tregs. These cells are known for their role in reducing inflammation, but now they have been found to also help reduce pain.

They do this by producing enkephalin, a natural opioid in the body, which acts by blocking pain signals in the spinal cord before they reach the brain. This blockage occurs by activating specific receptors in the neurons responsible for detecting pain, acting as a kind of natural "brake" on suffering.

When the researchers removed these Treg cells from the meninges of mice, they noticed something curious: the females became much more sensitive to pain, while the males were practically unaffected. This indicated that females rely more on this protective system to control pain.

To understand this better, the scientists investigated the relationship between these cells and female hormones. They discovered that estrogen and progesterone stimulate Treg cells to produce more enkephalin. Without these hormones, the Tregs' ability to control pain diminishes.

Furthermore, the researchers showed that it was possible to increase the number of these cells by injecting a substance called IL-2 into the spinal fluid of mice.

This reduced the sensitivity to pain in female mice that had suffered nerve damage. However, this effect disappeared when female hormones were blocked, confirming that the mechanism is indeed hormone-dependent.

These findings are important because they help explain why certain painkillers work differently in men and women and why postmenopausal women, who have lower levels of estrogen and progesterone, tend to have more problems with chronic pain.

In the future, understanding this mechanism could lead to the development of new therapies that harness the immune system itself to control pain, offering relief in a more natural way and with fewer side effects.

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Meningeal regulatory T cells inhibit nociception in female mice

ÉLORA MIDAVAINE, BEATRIZ C. MORAES, JORGE BENITEZ, SIAN R. RODRIGUEZ, JOAO M. BRAZ, NATHAN P. KOCHHAR, WALTER L. ECKALBAR,  LIN TIAN, ANA I. DOMINGOS, JOHN E. PINTAR, ALLAN I. BASBAUM, SAKEEN W. KASHEM 

SCIENCE, 3 Apr 2025, Vol 388, Issue 6742, pp. 96-104

DOI: 10.1126/science.adq65

Abstract:

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.