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 UCSF: The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health, which serves as UCSF's primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area. UCSF School of Medicine also has a regional campus in Fresno. Learn more at ucsf.edu, or see our Fact Sheet.
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