Summary: Researchers have discovered why migraines are often one-sided, revealing that proteins released during the aura are transported to pain-signaling nerves via the cerebrospinal fluid. The study highlights a new communication channel between the brain and the peripheral sensory nervous system.
These findings provide insight into the mechanisms of migraine and potential new treatments. This advance could lead to better therapies for people with migraines.
Highlights:
- Protein pathway: Brain proteins activate nerves that signal pain, causing migraines.
- One-sided pain: This new pathway explains why migraines are often one-sided.
- Treatment potential: Identified proteins could lead to new treatments for migraine.
Source: University of Copenhagen
More than 800,000 Danes suffer from migraine, a condition characterized by severe headaches on one side of the head. In about a quarter of migraine patients, headache attacks are preceded by an aura, i.e. cerebral symptoms such as temporary visual or sensory disturbances preceding the migraine attack by 5 to 60 minutes.
Although we know with some certainty why patients experience an aura, why they have headaches and why migraines are one-sided remains a mystery.
So far. A new study in mice by researchers at the University of Copenhagen, Rigshospitalet and Bispebjerg Hospital is the first to demonstrate that proteins released by the brain during migraine with aura are transported with the cerebrospinal fluid to the pain-signalling nerves responsible for headaches.
“We found that these proteins activate a group of sensory nerve cell bodies at the base of the skull, the trigeminal ganglion, which can be described as a gateway to the peripheral sensory nervous system of the skull,” says Martin Kaag Rasmussen, a postdoctoral fellow at the Center for Translational Neuromedicine at the University of Copenhagen, who is the study’s first author.
At the root of the trigeminal ganglion, the barrier that usually prevents substances from entering the peripheral nerves is missing, allowing substances from the cerebrospinal fluid to enter and activate the pain-signaling sensory nerves, causing headaches.
“Our results suggest that we have identified the main communication channel between the brain and the peripheral sensory nervous system. This is a previously unknown signaling pathway that is important for the development of migraine, and it may also be associated with other headache-related diseases,” says Professor Maiken Nedergaard, lead author of the study.
The peripheral nervous system consists of all the nerve fibers responsible for communication between the central nervous system (brain and spinal cord) and the skin, organs, and muscles. The sensory nervous system, which is part of the peripheral nervous system, is responsible for communicating information such as touch, itching, and pain to the brain.
The study results help explain why migraine is usually unilateral, which remains a mystery to scientists.
“Most patients suffer from unilateral headaches and this signaling pathway may help explain why. Our study on brain protein transport shows that substances are not transported throughout the entire intracranial space, but mainly in the sensory system on the same side, which is the cause of unilateral headaches,” says Martin Kaag Rasmussen.
The study was conducted on mice, but also included MRI scans of the human trigeminal ganglion, and according to the scientists, everything indicates that the function of the signaling pathway is the same in mice and humans and that, in humans too, the proteins are transported by the cerebrospinal fluid.
Proteins could open the door to new therapeutic options
Using cutting-edge techniques such as mass spectrometry, which can detect a wide selection of proteins in a given sample, the researchers analyzed the cocktail of substances released during the aura phase of a migraine attack, that is, during the phase of visual disturbances.
“The concentration of 11% of the 1,425 proteins we identified in the cerebrospinal fluid changed during migraine attacks. Of these, 12 proteins whose concentration increased acted as transmitter substances capable of activating sensory nerves,” explains Martin Kaag Rasmussen, who adds:
“This means that when the proteins are released, they are transported to the trigeminal ganglion via said signaling pathways, where they bind to a receptor on a pain-signaling sensory nerve, activating the nerve and triggering the migraine attack that follows the aura symptoms.”
Among the proteins identified by the researchers was the CGRP protein, already associated with migraine and used in existing treatments. However, the researchers also discovered a series of other proteins, which could open the way to new therapeutic options.
“We hope that the proteins we have identified – in addition to CGRP – can be used in the design of new preventive treatments for patients who do not respond to available CGRP antagonists. The next step for us is to identify the protein with the greatest potential,” says Martin Kaag Rasmussen.
He explains that one of the proteins identified is known to play a role in menstrual migraine.
“Initially, we hope to identify the proteins that trigger migraine phenotypes. We will then conduct challenge tests in humans to determine whether exposure to any of the identified proteins can trigger a migraine attack,” explains Martin Kaag Rasmussen, who adds:
“It’s a good idea to test whether this and other proteins can trigger migraine attacks in humans, because if so, they could be used as targets in treatment and prevention.”
About this migraine and neurology research news
Author: Sasha Kael
Source: University of Copenhagen
Contact: Sascha Kael – University of Copenhagen
Picture: Image credited to Neuroscience News
Original research: Access closed.
“Trigeminal ganglion neurons are directly activated by CSF solute influx in a migraine model” by Martin Kaag Rasmussen et al. Science
Abstract
Trigeminal ganglion neurons are directly activated by CSF solute influx in a migraine model
Patients with classic migraines experience aura, which is a transient neurological deficit associated with diffuse cortical depression (DCD), preceding headache attacks. It is currently unclear how a pathological event in the cortex can affect peripheral sensory neurons.
In this study, we show that cerebrospinal fluid (CSF) flows into the trigeminal ganglion, establishing non-synaptic signaling between the brain and trigeminal cells.
After CSD, approximately 11% of the CSF proteome is altered, with upregulation of proteins that directly activate trigeminal ganglion receptors. CSF collected from CSD-exposed animals activates trigeminal neurons in naive mice partly through CSF-mediated calcitonin gene-related peptide (CGRP).
We identify a communication pathway between the central and peripheral nervous system that could explain the relationship between migraine aura and headache.