Migraine is a chronic and debilitating neurological condition that affects women three to four times more often than men.
Despite affecting an estimated 1.1 billion people worldwide, the exact causes of migraines remain unclear, though they are widely studied.
Researchers from the UNC School of Medicine have made a significant discovery about how a small protein called calcitonin gene-related peptide (CGRP) influences the lymphatic vascular system, contributing to migraine pain.
Their findings were published in the Journal of Clinical Investigation.
Dr. Kathleen M. Caron, a leading researcher in the study, explained that their research has shown the importance of the brain’s lymphatic system in migraine pain.
They found that migraine pain is influenced by changes in interactions with immune cells and by CGRP preventing cerebrospinal fluid (CSF) from draining out of the brain’s lymphatic vessels.
CGRP, a small protein involved in pain transmission, is known to be elevated in the layers of tissues surrounding the brain (the meninges) during migraine attacks.
The team discovered that increased CGRP levels also significantly affect the brain’s lymphatic vessels, which help remove CSF and create pathways for immune cells to protect the brain.
To understand how CGRP influences the lymphatic system and contributes to migraine pain, the researchers conducted numerous experiments in the lab and in live animals. Nate Nelson-Maney, a MD-Ph.D. student, led these experiments.
Using mouse models immune to the effects of CGRP, they found that these mice experienced less pain and spent more time in brightly lit areas compared to mice sensitive to CGRP. Bright light is a painful stimulus for people with migraines, and similar behavior in mice confirms the study’s relevance.
The researchers also used cell culture techniques to examine how a protein called VE-Cadherin is arranged between the cells lining the lymphatic vessels. VE-Cadherin helps keep these cells together and controls how much fluid, like CSF, can pass between them.
They found that when lymphatic endothelial cells are treated with CGRP, their VE-Cadherin proteins align tightly, like a zipper on a jacket, preventing fluid from passing between cells and reducing the permeability of these cell layers.
This finding was validated in the meningeal lymphatic tissue of mouse models with nitroglycerin-induced migraines. When CGRP and a traceable dye were injected into the meningeal lymphatic vessels, there was a significant reduction in the amount of CSF exiting the skull.
Future studies will explore the relationships between migraines, CGRP, and meningeal lymphatic vessels further.
The research team aims to understand how CSF drainage through these vessels contributes to migraines in humans, including studies with and without the use of FDA-approved CGRP-targeting medications like Nurtec, Emgality, and Ajovy.
Although CGRP is identified as a key factor in migraine-related changes to the lymphatic system, researchers do not fully understand all the triggers and pain mechanisms of migraines.
More research is needed to understand how meningeal lymphatic vessels and the hormone-related life stages of women, such as puberty, pregnancy, and menopause, contribute to migraines.
Dr. Caron also pointed out that lymphatic dysfunction is more common in women, suggesting that neurological disorders like migraines might be influenced by sex differences in the meningeal lymphatic vasculature.
If this is true, new treatments targeting these lymphatic pathways could be beneficial, especially for women.
This groundbreaking research opens new avenues for understanding and treating migraines, offering hope for better management of this painful condition.
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The research findings can be found in the Journal of Clinical Investigation.
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