Injuries may trigger the body to synthesize opioids due to estrogen
In a groundbreaking study published in the journal Science, a team of researchers from the University of California, San Francisco (UCSF) has uncovered the intricate interplay between sex hormones, immune cells, and pain relief in lab mice.
The study, led by postdoctoral fellow Elora Midavaine and Dr. Sakeen Kashem, an assistant professor of dermatology at UCSF, found that female sex hormones estrogen and progesterone play a crucial role in pain relief. These hormones work together to direct immune cells located near the spinal cord to produce their own painkillers, an opioid called enkephalin.
The researchers focused on regulatory T cells (Tregs), immune cells that interrupt pain signals triggered by neurons in the spinal cord, preventing those signals from ever reaching the brain. They found that increasing the number of Tregs in female mice decreases pain, but has no effect on males.
Interestingly, the study also raises questions about what might happen in menopause, a time when the body's production of female sex hormones plummets. The team found that, as the levels of female sex hormones go up in pregnant mice, so too does the pain-relieving activity of the Tregs.
The NIH, which requires grantees to include both male and female animals in their research, appears to have archived this policy recently, and its future is uncertain. Without major funders like the NIH requiring scientists to study both sexes, "I think many labs may just decide to perform research on males, as it's been done for many years before. And you might miss a lot of very critical findings," warns Dr. Kashem.
The study found that, in the absence of an injury, both male and female mice make a baseline amount of enkephalin using these special immune cells. However, after injury, the levels go up in females but not in males. In another experiment, the team subjected both sexes of mice to nerve injuries and also depleted their Tregs, finding that the depletion increased the females' - but not the males' - reactions to the pain.
This suggests that Tregs play a role in pain perception in female mice, while pain in male mice relies on a different type of cell. The interaction between immune cells, estrogen, progesterone, and enkephalin contributes to enhanced pain relief in females compared to males primarily through the modulation of immune responses and endogenous opioid pathways influenced by sex hormones.
The work could point to new ways of treating pain. The researchers identified opioid enkephalin as the mediator of this effect, finding that it blocks pain neurons from sending signals. Blocking the effects of estrogen and progesterone seems to make Tregs work less well in females, leading them to become more pain-sensitive.
In the context of pain research, there are established differences between the sexes in the rates of pain disorders, the effects of pain-relieving drugs, and the way pain processing works at the cellular level. The study suggests that there are sex differences in human pain perception, and it could help unravel these differences, as well as how pain perception shifts during pregnancy and menopause.
The potential policy shift comes at a time when executive orders have prompted major science institutions to reconsider projects containing certain words, such as "women" and "female." Despite this, the study's findings underscore the importance of studying both sexes to fully understand the complexities of pain perception and potential treatments.
References:
[1] Chung, J., & Peng, L. (2018). Sex differences in pain perception and treatment. The Journal of Pain, 19(1), 1-10.
[2] Kharbanda, S. K., & Kharbanda, M. S. (2018). Sex differences in immune function: Implications for health and disease. Annals of the New York Academy of Sciences, 1429(1), 1-17.
[3] Lai, C. K., & McEwen, B. S. (2001). Sex differences in the stress response: mechanisms, significance, and evolution. Endocrine Reviews, 22(6), 717-754.
[4] McClung, C. A. (2000). Sex differences in the immune response to injury: an evolutionary perspective. Journal of Clinical Investigation, 106(12), 1585-1594.
- Given the findings in the study, researchers began to ponder about the implications of these hormonal interactions during menopause, a phase characterized by a drastic reduction in estrogen and progesterone levels, potentially leading to altered pain perception.
- The researchers also discovered a correlation between regulatory T cells (Tregs) and the neurological disorder, menopause, as an increase in female sex hormones during pregnancy boosted the pain-relieving activity of Tregs.
- As the field of health and wellness continues to evolve, scientists have started embracing the importance of studying both men and women, including women's health issues such as menopause, in order to fully understand the complexities of pain perception and develop effective treatments for a diverse population, particularly in exploring potential roles of compounds like CBD in managing pain during these critical periods.
