Researchers Identify Signaling Pathway Responsible for Migraine Attacks with Aura

Investigators from the University of Copenhagen have found a previously unknown signaling pathway in the brain showing how proteins are carried to a group of sensory neurons that cause migraine attacks. The mouse study, conducted at Rigshospitalet and Bispebjerg Hospital in Denmark was published in the journal Science.

The researchers focused on discovering why patients who experience aura, characterized by temporary visual or sensory disturbances, precede migraine attacks by five minutes to an hour in roughly 25% of all people with migraines. Their work found that proteins released from the brain during migraine with aura are travel via cerebrospinal fluid (CSF) to the pain signaling nerves that cause headaches.

“We have discovered that these proteins activate a group of sensory nerve cell bodies at the base of the skull, the so-called trigeminal ganglion, which can be described as a gateway to the peripheral sensory nervous system of the skull,” says first author postdoctoral researcher Martin Kaag Rasmussen, PhD, from the Center for Translational Neuromedicine at the University of Copenhagen.

The barrier that normally prevents substances from entering the peripheral nerves is missing at the base of the trigeminal ganglion. This allows the CSF to enter and activate the pain signaling sensory nerves.

“Our results suggest that we have identified the primary channel of communication between the brain and the peripheral sensory nervous system. It is a previously unknown signalling pathway important for the development of migraine headache, and it might be associated with other headache diseases too,” noted professor Maiken Nedergaard, PhD, the senior author of the study.

The peripheral nervous system is composed of nerves and fibers that provide the two-way communication between it and the central nervous system. The sensory nervous system communicates sensations such as touch, itching, and pain to the brain. The study also provided new insights as to what migraine is usually felt on one side of the head, the answer to which has eluded scientists.

Most patients experience one-sided headaches, and this signalling pathway can help explain why. Our study of how proteins from the brain are transported shows that the substances are not carried to the entire intracranial space, but primarily to the sensory system in the same side, which is what causes one-sided headaches,” said Rasmussen.

For this research the Danish team used mass spectrometry to analyze a samples from mouse model to detects proteins that are release during the aura phase that precedes migraines. From these samples and analysis, the team showed that roughly 11% of the 1,425 proteins identified CSF during migraine attacks. Of that population the team identified 12 that are transmitted substance capable of activating sensory nerves.

“This means that when the proteins are released, they are carried to the trigeminal ganglion via the said signaling pathways, where they bind to a receptor of a pain-signalling sensory nerve, activating the nerve and triggering the migraine attack succeeding the aura symptoms,” Rasmussen said.

One of the dozen proteins is CGPR, one that has already been associated with migraine in previous research and used in existing migraine therapies, but other proteins in the group could also be new targets for future treatments.