A groundbreaking study from researchers at UC San Francisco has revealed how female hormones play a role in pain suppression by prompting immune cells to produce opioids, offering new hope for chronic pain treatment.
The research, published in Science on April 4, discovered that female hormones, specifically estrogen and progesterone, influence immune cells near the spinal cord to produce opioids, effectively blocking pain signals before they reach the brain. This mechanism could lead to the development of more targeted treatments for chronic pain and help explain why certain pain medications are more effective for women than men.
The study, led by postdoctoral fellow Elora Midavaine, PhD, and co-led by Sakeen Kashem, MD, PhD, and Allan Basbaum, PhD, highlights the role of T regulatory immune cells (T-regs) in managing pain. T-regs are well-known for their ability to reduce inflammation, but this research reveals a new function for these cells in pain regulation—one that is influenced by sex hormones.
Dr. Midavaine explained, “The fact that there’s a sex-dependent influence on these cells—driven by estrogen and progesterone—and that it’s not related to any immune function is very unusual.”
Researchers focused on T-regs in the meninges, the protective layers surrounding the brain and spinal cord. These tissues, previously thought to solely protect the central nervous system, were found to also play a role in communicating with neurons that detect pain signals. The discovery marks an important shift in understanding how the immune system interacts with sensory neurons.
When the team removed T-regs from the meninges using a toxin, they observed a significant difference: female mice became more sensitive to pain, while male mice showed no such change. This suggests that female mice depend more on T-regs to manage pain.
“We were both fascinated and puzzled by this,” said Dr. Kashem. “It actually made me skeptical at first.”
Further experiments revealed that estrogen and progesterone prompted the T-regs to produce enkephalin, a natural painkiller. The exact mechanism behind this hormone-driven process remains a mystery, but the findings suggest a sex-specific pathway for pain regulation.
This discovery has important implications for personalized pain treatment. In the short term, it could help doctors tailor pain medications to a patient’s sex. For example, certain migraine treatments have been shown to work better in women than men. The research could also explain why many postmenopausal women experience chronic pain, as their bodies no longer produce estrogen and progesterone.
The team is now exploring the possibility of engineering T-regs to produce enkephalin constantly, which could provide long-term relief for both men and women suffering from chronic pain.
“If successful, this approach could significantly improve the lives of the nearly 20% of Americans who experience chronic pain that is not adequately treated,” said Dr. Basbaum.
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