The scientific community has long known that migraine is more common in women. It’s also known that certain chemicals reliably trigger migraines. No one contradicts these ideas, but no one knows why either is true.
Researchers at The University of Texas at Dallas are using new tactics to analyze these old truths, with the hope of learning more about the mechanisms behind a condition believed to plague more than 10 percent of people worldwide.
Dr. Greg Dussor, Fellow, Eugene McDermott Professor in the School of Behavioral and Brain Sciences, is the principal investigator on two National Institutes of Health (NIH) grants — totaling more than $2.8 million across five years — to pursue these answers.
“These two projects ask questions about widely acknowledged observations,” Dussor said. “Migraine is more common in women. Why? We don’t know. Nitric oxide donors — substances that release that compound — reliably trigger migraines in people. Again, we don’t know why. These are inarguable conclusions from which we have to work backward.”
Migraine is a condition defined by severe periodic headaches that can be accompanied by nausea, vision disturbances and sensitivity to light or sound.
Prolactin, the Perpetrator?
The first of the two studies — both conducted in animal models and funded by the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) — is a collaboration with Dr. Armen Akopian, associate professor of endodontics at the UT Health Science Center at San Antonio. Dussor and Akopian are investigating a link between migraine and the hormone prolactin, most associated with milk production in mammals. Prolactin also affects metabolism, the immune system and more.
The period during which women suffer migraine attacks strongly suggests a tie to reproductive hormones, Dussor said.
“Before puberty and after menopause, men and women have about the same prevalence for migraine,” he said. “In between, females’ migraine rate increases dramatically. Many women also have days of their menstrual cycle that are conducive to migraine, or dramatic shifts in attacks during pregnancy.”
While he does not believe prolactin is the cause behind all migraines, Dussor hypothesizes that the hormone is a predisposing factor making migraine more likely.
“No one has identified the primary driver of migraine attacks,” he said. “Whatever that is, it might be the same in males and females, or that initial cause itself might be different.”
In Dussor’s earlier animal studies, female subjects showed a clear migraine response to prolactin, while males showed none at all.
“Those findings energized the project — to see something so strikingly different,” Dussor said.
If prolactin is shown to make migraine headaches worse, he said, the most straightforward therapeutic would block prolactin receptors.
“That would make it female-specific, which is interesting — that’s not how therapeutics work today,” Dussor said. “Your potential market is cut in half, but that’s fine, because the skew of migraine toward women is so severe.”
Even if such a blocker is successful, Dussor said limitations would apply.
“You’re not going to use these in pregnant women or in women who may become pregnant,” he said. “But there already are therapeutics that have those kinds of cautions. And I think that many patients would be willing to deal with these limitations if they get relief.”
Dussor credited a pilot grant from The University of Texas System for getting this project rolling.
“In 2015, Dr. Akopian and I received a UT Brain Seed Grant because this was a collaboration between two UT campuses,” he said. “These grants help generate the preliminary data needed to get a larger grant. It was a forward-looking strategy by the UT System, and it made us competitive for the NIH grant.”
The second NINDS study builds off the knowledge that, in three out of four migraine patients, drugs that create nitric oxide in the body cause a migraine within six hours. Those drugs include nitroglycerin, given almost exclusively to counteract chest pain by dilating blood vessels.
“We’ve known since nitroglycerin was first synthesized in 1847 that it was a very reliable trigger of migraine attacks, but we don’t know what mechanism causes the attacks,” Dussor said.
Dussor and his team want to determine which of nitric oxide’s metabolic products is relevant to migraine, focusing on a nitrogen radical called peroxynitrite.
“Peroxynitrite is produced when nitric oxide reacts with superoxide, a negatively charged oxygen molecule,” Dussor said. “We chose peroxynitrite because we already know how to neutralize it, and because targeting it should not have major side effects. Some products of nitric oxide can’t be safely targeted.”
Though nitric oxide has many products, Dussor said that trying to find the correct one was worthwhile.
“We have to take a shot, pick one and look closely at it,” he said. “Maybe all we do is cross one item off the list, and someone else can start with the next one.”
Turning Over Every Rock
In pursuing these advances, Dussor emphasized that there may never be a single drug that works for every migraine patient.
“Drugs for other types of pain don’t work that well on migraine. Meanwhile, triptans, the drugs given for migraine attacks, aren’t given for any other type of pain,” he said. “There’s excitement around CGRP (calcitonin gene-related peptide) inhibitors right now. There are three new Food and Drug Administration-approved therapeutics based on that mechanism, and those will help a lot of people. But it’s already clear that they don’t work in everybody.
“A high percentage of the migraine population gets zero or little relief from current therapeutics. We need as many solutions as we can come up with.”