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Doctors may be able to develop new treatments for migraines and chronic pain in women by targeting receptors in the brain that help regulate their fertility, new research from the University of Virginia School of Medicine suggests.

The receptors respond to the hormone progesterone, which is used in birth control pills to prevent pregnancy. Those pills have been known to promote headaches in some women, and UVA’s new research reveals how the hormone may have the unexpected ability to promote pain sensitivity.

“We have known for a long time that women are more likely to suffer from migraine headaches. This study explains their vulnerability to this common, disabling pain,” said UVA Health neurologist Jaideep Kapur, MD, PhD, co-director of the UVA Brain Institute. “We hope to develop novel therapies to prevent and treat migraines in women by focusing on the receptor and its downstream effects.”

Pain in Women

Migraines are more likely to strike women than men. Roughly one in five women is thought to suffer from these potentially debilitating headaches, compared with fewer than one in 10 men. Further, women are more likely than men to develop chronic pain during their reproductive years.

UVA’s new research may help explain why. The findings suggest that progesterone receptors in the brain help regulate pain perception. Activation of the receptors promotes pain susceptibility, the new research suggests. 

Further, the findings bolster the notion that reproductive hormones such as estrogen and progesterone play an important role in pain susceptibility in women.

“The discovery of progesterone receptor expression beyond the hypothalamus, particularly in regions associated with pain processing and migraine pathophysiology, opens new avenues for understanding the role of progesterone in pain modulation,” said researcher Suchitra Joshi, MSc, PhD. “We can potentially modulate neuronal activity, synaptic transmission and pain sensitivity by targeting these receptors in the brain regions involved in migraine pain processing. Compared to broader systemic treatments, this targeted approach may offer more precise and effective therapeutic interventions to alleviate migraine pain and improve the quality of life for individuals affected by this debilitating condition.”

Prior scientific research had suggested that progesterone might help control pain susceptibility, but results have been inconsistent: Progesterone appeared to reduce pain sensitivity in some instances but not all. Other research suggested it might have the opposite effect. Efforts to use progesterone to help manage pain in people also have produced mixed results. 

UVA’s new research may help explain that. The pain-sensitizing effects caused by activating progesterone receptors in the brain may undercut the pain-reducing effects of a particular progesterone molecule, or “metabolite,” called pregnanolone.

The researchers say their new understanding of the complex relationship between pain and progesterone and its receptors could pave the way for new ways to treat and manage chronic pain and migraines in women. Researchers might use drugs, for example, to reduce pain sensitivity by blocking the activation of the progesterone receptors. 

“In the future, we may be able to prevent headaches when women are most likely to suffer from them by targeting these receptors,” said Kapur, of UVA’s Department of Neuroscience. “Blocking progesterone receptor-regulated signaling in the brain presents a promising avenue for novel migraine treatment, particularly in women during their reproductive years. Progesterone's influence on neuronal activity involves various signaling pathways and mechanisms. By targeting progesterone receptors, researchers and clinicians can potentially modulate these pathways to mitigate migraine and other chronic pain conditions.

“However, further research is needed to elucidate the precise mechanisms by which progesterone receptors contribute to migraine pathogenesis and to develop targeted pharmacological interventions that can effectively modulate these pathways.” 

Findings Published

The researchers have published their findings in the Journal of Pain. The research team consisted of Joshi, John Williamson, Shayan Moosa and Kapur. The scientists have no financial interest in the work.

The research was supported by the National Institutes of Health, grants

R01NS110863, R01NS120945 and R37NS119012.

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