Blockages in the brain’s plumbing system may finally explain painful migraines
A new study has found the potential cause of migraines, explaining why they hurt so much and revealing how to treat them.
If you’ve ever experienced a migraine, you know it’s more than just a headache. For the millions who suffer from this debilitating condition, relief can seem out of reach. Now, however, researchers from the University of North Carolina School of Medicine may be able to change that. Their study published in the Journal of Clinical Investigation has found the potential cause of migraines, explaining why they hurt so much and revealing how to treat them.
The culprit? A small protein called calcitonin gene-related peptide, or CGRP for short. While scientists have known about CGRP’s involvement in migraine pain for a while, this new study reveals its surprising impact on the brain’s plumbing system.
“Our study has highlighted the importance of the brain’s lymphatic system in the pathophysiology of migraine pain,” says Kathleen M. Caron, PhD, the Frederick L. Eldridge Distinguished Professor and chair of the Department of Cell Biology and Physiology and senior author on the study, in a media release. “We found that migraine pain is influenced by altered interactions with immune cells and by CGRP preventing cerebrospinal fluid from draining out of the meningeal lymphatic vessels.”
So, what does all that mean for migraine sufferers? Let’s break it down.
Your brain has its own drainage system, kind of like the pipes in your house. This system is called the lymphatic system, and it helps remove excess fluid (cerebrospinal fluid) and allows immune cells to patrol the brain’s protective layers. During a migraine attack, CGRP levels spike in these areas.
The UNC team discovered that this CGRP surge doesn’t just affect pain signals — it actually changes how the brain’s drainage pipes work. It’s like CGRP acts as a molecular wrench, tightening up the pipes so that fluid can’t flow as easily.
To investigate this, the researchers used some clever techniques. They studied mice that were resistant to CGRP’s effects and found these mice experienced less pain and were more comfortable in bright light (a common migraine trigger) compared to normal mice.
Then, zooming in even closer, they looked at the cells lining the lymphatic vessels. These cells have a special protein called VE-Cadherin that acts like Velcro, keeping the cells stuck together. When exposed to CGRP, this cellular Velcro rearranges into a super-tight formation, preventing fluid from passing through.
Nate Nelson-Maney, the study’s first author and an MD-PhD student, led these experiments. The team confirmed their findings by observing actual brain tissue from mice with induced migraines. When they injected CGRP and a traceable dye into the lymphatic vessels, they saw a significant reduction in fluid drainage from the skull.
“Since lymphatic dysfunction also exhibits a strong prevalence in women, it is tempting to speculate that neurological disorders like migraine could be governed by sex differences in the meningeal lymphatic vasculature,” says Caron, who is also a member of the UNC Lineberger Comprehensive Cancer Center. “If this were true, then new therapeutic strategies or drug targets that enhance meningeal lymphatic and glymphatic flow in women would be desirable.”
While this research is a big step forward, there’s still more to learn. The UNC team plans to investigate how this impaired fluid drainage relates to migraine in humans, potentially working with patients using newer CGRP-targeting medications like Nurtec, Emgality, and Ajovy.
The study also raises intriguing questions about why migraines affect women so much more frequently than men. Could hormonal changes throughout a woman’s life influence this brain drainage system? Future research might explore connections between the lymphatic system and female-specific life stages like puberty, pregnancy, and menopause. For the millions living with migraines, this research offers hope. By understanding the intricate mechanisms behind the pain, scientists are one step closer to developing more effective treatments.
The study used a sophisticated genetic approach involving mice specifically modified to lack the CGRP receptor — a critical component in migraine pathology — only in their meningeal lymphatic vessels. This targeted approach allowed researchers to isolate the effects of blocking CGRP signaling in lymphatics, distinguishing it from other tissues.
The mice underwent a series of treatments to induce migraine-like symptoms, and their responses were compared to those of normal, control mice. Pain responses were measured using the murine grimace scale, a reliable indicator of pain based on facial expressions.
Key Results
Mice with the CGRP receptor knocked out in their meningeal lymphatics showed significantly less pain and reduced aversive reactions to light — a common migraine symptom — compared to their normal counterparts. This suggests that CGRP’s role in the lymphatic system is crucial in mediating migraine symptoms. Additionally, treatments targeting CGRP signaling in these specific lymphatic vessels could mitigate the intensity of migraine pain.
Study Limitations
While the study presents compelling evidence on the role of meningeal lymphatics in migraines, its findings are primarily based on animal models, which might not fully replicate human migraine pathophysiology. The study also doesn’t explore the potential side effects of long-term CGRP receptor blocking, which could have implications for lymphatic function more broadly.
This research opens up a new avenue in migraine treatment by highlighting the meningeal lymphatics as a potential target for therapeutic intervention. The findings suggest that treatments aimed at modulating CGRP signaling in the lymphatic system could offer new hope for those suffering from chronic migraines. Furthermore, understanding the interaction between meningeal lymphatics and migraine symptoms could lead to more effective preventive strategies and reduce the burden of this debilitating condition.
In summary, the study not only sheds light on the understudied role of meningeal lymphatics in migraine pathology but also proposes a potential new target for migraine therapies. This could lead to more precise and effective treatments, bringing relief to millions of migraine sufferers worldwide.
