Scientists Uncover Key Stress Pathway Driving Migraines

Migraines are more than just bad headaches; they stem from a genetic neurological disease that causes suffering for one in seven people. Those who experience migraines can have a myriad of debilitating symptoms, including pain, nausea, sensitivity to light and visual disturbances that prevent them from participating in work and family life. Pain is one way our body warns us something is wrong, but what do we do when this alarm system prevents us from living life fully?

A scientist at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) has discovered a pathway triggered in the brain during stressful situations. Halting this process at an early stage could prevent the domino effect that leads to migraines.

A study published in the Journal of Headache and Pain, led by Yu Shin Kim, PhD, associate professor in the Department of Oral & Maxillofacial Surgery, School of Dentistry, UT Health San Antonio, shows how stress causes an increase in levels of a potent neuropeptide called pituitary adenylate cyclase-activating polypeptide-38 (PACAP38). This neuropeptide couples with a certain mast cell receptor (MrgprB2), causing cells to release inflammatory substances. Mast cells work like a sort of speaker system, amplifying incoming messages. This series of effects lead to increased sensitivity in the trigeminovascular system of the dura, a thin membrane of connective tissue that covers the brain and spinal cord, leading to headaches and/or migraine pain.

Where it all begins

PACAP38 plays a large part in regulating stress levels in the body. After stress-inducing situations, the blood is flooded with PACAP38, which is correlated with the onset of migraines. Kim’s study shows that in mouse models lacking the mast cell receptor MrgprB2, mice did not display trigeminovascular system sensitivity after stress and did not have mast cell activation. This means that preventing the PACAP38-MrgprB2 connection could be a promising target for the treatment of stress-induced migraines.

For the study, both non-altered control mice and MrgprB2-deficient mice received PACAP38 and were exposed to repetitive stress. Researchers then examined them externally and internally. They found that non-altered mice exhibited migraine symptoms, but MrgprB2-deficient mice did not show trigeminal sensitization or mast cell activation and did not appear to have migraine pain.

How and why of migraines

Along with how stress-induced migraines begin, this study also investigates why people have migraines in the first place. Kim explains that our bodies regulate internal functioning through a process called interoception. The body aims to maintain homeostasis by monitoring and responding to changes occurring within it. When there are stressors in a person’s environment, for example, the body responds by releasing certain hormones as a warning that something is wrong and needs correction.

“This hormone and peptide are manipulating the system to warn you that you have to go in a different direction, otherwise your body will be in a bad condition,” Kim said.

Stress-migraine connection

In all animals, activation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in stressful situations, causing the animal to physically respond. In a similar fashion, hypothalamic activation also happens during the prodrome phase before migraine. Migraine sufferers show elevated cortisol levels, an HPA axis-regulated stress hormone, further pointing to the connection between migraines and stress. Kim said migraines could be the body’s way of telling a person to stop and deal with a stressor.

“Without this warning system, a person may remain in stress-inducing situations that could cause damage, injury or even death to the body,” Kim said. Over time, stress-induced migraines may have been beneficial by causing humans to relax, get more sleep or otherwise take measures to regain their homeostasis, he said.

Scientists are not sure why some people get migraines and others do not, or why migraines are more common in women. About 15% of people experience migraines, with women being three times more likely to get them. Migraines generally occur in women between the ages of 20 and 50, so scientists are also investigating how hormones and hormonal changes may play a part in migraine development.

Kim said that for people who suffer from migraines, there is likely a host of interrelated factors leading to the condition. Vasodilator drugs that block the calcitonin gene-related peptide provide relief for about half of migraine sufferers, but for the other half, these drugs are ineffective.

This study shows that PACAP38 leads to stress-induced migraines through the MrgprB2-Mast cell pathway and not through other receptors like PAC1, as previously thought. Treatments that block PACAP38 from connecting to MrgprB2 to prevent the initiation of this painful process could provide a new avenue of hope for migraine sufferers.

Reference: Son H, Zhang Y, Shannonhouse J, Gomez R, Kim YS. PACAP38/mast-cell-specific receptor axis mediates repetitive stress-induced headache in mice. J Headache Pain. 2024;25(1):87. doi: 10.1186/s10194-024-01786-3

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