Estrogen and Progesterone Regulate Natural Opioids in Women

Why do women and men experience pain differently? A study from researchers at the University of California - San Francisco (UCSF) suggests it may be down to your hormones.

Published in Science, the study found that T cells produce natural opioids that suppress pain signals – a process influenced by female hormones.

The urgent need for new chronic pain treatments

​Chronic pain affects millions worldwide, significantly diminishing the quality of life. Traditional treatments, particularly opioid medications, have been the cornerstone of pain management. While effective in the short term, opioids carry substantial risks, including dependence, tolerance and addiction. The opioid crisis has underscored the urgent need for safer, more sustainable pain relief solutions.

Researchers have been exploring non-opioid alternatives that target different aspects of pain processing. One promising avenue involves the interplay between the nervous and immune systems in pain modulation. The immune system is most recognized for its role in defending against pathogens, however, it has also been found to influence pain perception. Immune cells can release cytokines and other mediators that  exacerbate or alleviate pain. This dual role suggests that modulating immune responses could offer novel strategies for pain management. ​

Recent studies have highlighted the role of T cells, a subset of immune cells, in pain regulation. T cells have been implicated in both the amplification and resolution of pain. However, the exact mechanisms by which T cells influence pain processing are yet to be fully understood. ​

The meninges – the protective membranes enveloping the brain and spinal cord – were once thought to serve merely as structural barriers. However, recently, studies have revealed that the meninges house a distinct population of regulatory T cells (T-regs). These cells play a role in maintaining central nervous system homeostasis and modulating inflammatory responses. The discovery that T-regs reside in the meninges suggests an underexplored link between the immune system and pain regulation.

A discovery in pain regulation

To investigate the role of T-regs in pain regulation, the team conducted a series of experiments on mice. They first examined the distribution of T-regs in the meninges surrounding the spinal cord using immunostaining techniques.

They observed that T-regs were abundant in the lower spinal cord region, where pain-processing neurons receive sensory information. Until now, the meninges were not considered a site for immune-neural communication.

“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. This is something we hadn’t known before,” said Dr. Sakeen Kashem, an assistant professor of dermatology at UCSF.

To determine whether these cells played a role in pain modulation, the researchers selectively removed T-regs using a toxin and then measured the animals’ pain sensitivity using standard pain tests.

After T-reg removal, female mice became significantly more sensitive to pain, reacting more quickly to both heat and mechanical pressure. Male mice, however, showed no change.

Since only female mice showed a hypersensitivity to pain after T-reg depletion, researchers hypothesized that female hormones – estrogen and progesterone – might regulate T-reg function. To test this, they compared pain responses in female mice at different stages of their hormonal cycle and in mice that had their ovaries removed.

They found that pain sensitivity was highest when estrogen and progesterone levels were low. When the hormones were reintroduced, pain sensitivity decreased.

“It was both fascinating and puzzling,” said Kashem. “It actually made me skeptical initially.” 

“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 first author Dr. Elora Midavaine, a post-doctoral researcher at UCSF.

The researchers also analyzed the molecular activity of T-regs using RNA sequencing and protein analysis. They discovered that the cells in female mice were producing high levels of enkephalin – a natural opioid that binds to pain-suppressing receptors in the spinal cord. Enkephalin binds to the same receptors as morphine.

When the team blocked these opioid receptors, the pain-relieving effect of T-regs disappeared.

Midavaine and colleagues also tested whether T-reg depletion affected inflammation-related pain markers and found no change, suggesting that the pain relief is due to enkephalin, not general immune suppression.

Implications for future pain treatments

The discovery that T-regs in the meninges produce natural opioids under hormonal influence opens exciting possibilities for new pain treatments. By understanding how the immune system naturally suppresses pain, researchers may be able to develop novel therapies that work with the body’s own mechanisms rather than relying on traditional painkillers like opioids.

If T-regs can be stimulated to produce more enkephalin, this could provide a natural and long-lasting form of pain relief.

This discovery could be especially significant for postmenopausal women, who often experience increased pain due to declining estrogen and progesterone levels. Without these hormones, their T-regs may no longer produce as much enkephalin, leading to greater pain sensitivity. The results could also lead to non-opioid, immune-based pain therapies that specifically address hormone-related pain conditions, such as endometriosis.

Future research aims to focus on identifying the exact signaling pathways that allow estrogen and progesterone to boost enkephalin production.

The next step for the team is to explore whether T-regs can be engineered to produce enkephalin continuously, providing long-term, biologically driven pain relief.

“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,” said senior author Dr. Allan Basbaum, a professor and chair of the Department of Anatomy at UCSF.

If scientists can harness the power of T-regs to create targeted, hormone-sensitive pain treatments, this could change chronic pain management – offering a safer, more effective alternative to opioids for millions of people worldwide.

Reference: Midavaine É, Moraes BC, Benitez J, et al. Meningeal regulatory T cells inhibit nociception in female mice. Science. 2025. doi: 10.1126/science.adq6531

This article is a rework of a press release issued by the University of California - San Francisco. Material has been edited for length and content.