Basic Science of Migraine and Headache Update: New Mechanisms, New Targets, and More

Animal and cell studies continue to advance the field.

Editor’s note: One of our priorities at Migraine Science Collaborative is to provide in-depth coverage of the most important developments in basic science research in the migraine and headache field. Though small in comparison to related areas such as pain research, the community of basic scientists doing migraine research is vibrant and productive. In fact, fundamental discoveries made in the lab have helped spur the development of entirely new and successful drug classes – an enviable track record of success that fields focused on other neurological disorders have, unfortunately, been unable to achieve thus far.

To keep readers current with the latest developments, periodically we will provide a quick update on the most significant basic science research in migraine and headache – a synopsis of the most notable recent findings, many of which are covered in our news stories. Our goal is to provide a convenient way for readers to quickly get up to speed on the basic science that is moving things forward. This effort complements our more comprehensive biweekly literature recap of all the basic science, translational, and clinical studies that we think readers should be aware of.

We hope you enjoy the first edition, below, which covers some of the best work published so far in 2024, especially papers that received an Editor’s Pick designation in the biweekly recap.

New migraine mechanisms ripe for further study
Dysfunction of the lymphatic system – a network of lymph vessels, lymph nodes, and other structures – is associated with a host of neurological conditions, such as Alzheimer’s disease and multiple sclerosis. Two very important basic science studies now place migraine firmly in that group.

In one study, researchers led by Kathleen Caron (University of North Carolina, Chapel Hill, US) found that lymphatic vessels became less permeable in a mouse model of chronic migraine, which reduced the drainage of cerebrospinal fluid (CSF) to lymph nodes. Calcitonin gene-related peptide (CGRP) signaling appeared responsible for this, but also for an additional type of lymphatic dysfunction, namely, the entry of a particular type of T cell into meningeal lymphatic vessels.

In an MSC news story covering this work, our outside source, Dan Levy, a headache researcher at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, US, said: “This is awesome work that opens up the field to new targets for CGRP treatment or understanding how CGRP could work in migraine.”

Quick on the heels of those findings was another basic science study also showing a role for the lymphatic system in migraine. Here, as recounted in an MSC news story, using a cortical spreading depression model of migraine with aura, investigators led by Maiken Nedergaard (University of Copenhagen, Denmark, and University of Rochester Medical Center, US) and Martin Kaag Rasmussen  (University of Copenhagen) showed that CSF from the cortex could directly activate trigeminal ganglion nociceptors. Increased levels of a dozen proteins in the CSF – not only CGRP – were responsible for this activity. The findings suggest that, when it comes to migraine with aura mechanisms, activation of nociceptors in the dura mater is not the only game in town.

A trigeminal ganglion clock
Another significant basic science paper earlier this year also pointed toward the trigeminal ganglion. In this case, researchers led by Mark Burish and Seung-Hee Yoo (UTHealth Houston, US) found that trigeminal ganglion cells have a clock – a circadian rhythm. The cells showed a circadian rhythm in the genes they express, and the pain responses of mice also showed circadian features, in a nitroglycerin model of headache.

The study has important clinical implications, according to Greg Dussor (University of Texas at Dallas, US), the outside source for an MSC news story on the paper.

“The biggest strength [of the study] is the translational relevance of the circadian pattern of gene expression for common migraine drug targets. This kind of finding could lead to rapid translation to the clinic given the drugs are already in use; they just may not be given at the optimal time for efficacy” as things stand now, according to Dussor.

From sleep disruption to migraine? From migraine to sleep disruption? Both?
Does migraine influence sleep? Does sleep influence migraine? Or does the arrow point in both directions? Those questions were the focus of recent basic science work from Frank Porreca (University of Arizona, Tucson, US) and colleagues.

The team recorded the sleep of mice and assessed whether it was altered in response to nitroglycerin, inflammatory mediators, or umbellulone (a chemical irritant from the bay laurel tree, also known as the “headache tree”), all of which are substances that can produce migraine-like pain. Interestingly, sleep was unaffected in all of these preclinical models.

But when the researchers deprived mice of sleep, subthreshold nitroglycerin or dural CGRP led to migraine-like pain, as indicated by the presence of periorbital cutaneous allodynia in the animals.

In their paper, the researchers concluded: “Our data suggest that there is a directional causality in the relationship between migraine-like pain and sleep. While the pain phase of migraine does not disrupt sleep, sleep deprivation increases the likelihood of migraine-like pain…. Understanding and addressing the complex interplay between migraine and sleep may allow the implementation of therapeutic strategies including lifestyle modifications, behavioural interventions and pharmacological approaches to improve sleep quality for improved management of migraine.”

A new drug
A recent paper, from researchers at Purdue University, West Lafayette, US, and Washington University School of Medicine in St. Louis, US, reported the discovery of a new agonist that targets delta-opioid receptors (DORs). Thus far, DOR agonists have been unsuccessful in Phase 2 clinical trials, putting a damper on the promise of DORs as a drug target for neurological disorders like migraine and pain.

The newly identified agonist showed selective activity at the DOR, having little effect on other opioid receptors or on non-opioid G protein-coupled receptors (GPCRs; the class of receptor to which the DOR belongs). The selectivity of the agonist could mean that off-target effects can be avoided. The agonist also reduced pain in a mouse model of inflammatory pain.

Further exploration of a promising target
Speaking of drug targets, pituitary adenylate cyclase-activating peptide (PACAP) receptors have captured the attention of migraine researchers interested in replicating the success of targeting the CGRP system for migraine treatment. A new study from Sarah Louise Christensen (Copenhagen University Hospital – Rigshospitalet and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, US) and colleagues elucidates some of the workings of the PACAP system, providing relevant insight toward efforts to target it.

The new work sought to understand the roles that each of the three PACAP receptors – PAC1, VPAC1, and VPAC2 – plays in migraine. The investigators used a mouse model of migraine in which PACAP-38 is injected systemically, after which they would measure hind paw sensitivity. The study used three different “knockout” mouse strains, each missing one of the three receptors (PAC1 knockouts, VPAC1 knockouts, or VPAC2 knockouts).

PACAP-38 caused tactile hypersensitivity in control animals, but not in knockout mice missing VPAC1 or VPAC2. But PACAP-38 did produce hypersensitivity in knockout mice missing PAC1, just as it did in controls. Mice missing VPAC1 or VPAC2 showed reduced vasoactivity of the carotid artery, whereas mice missing PAC1 were no different from control animals on that measure.

The decreased response to PACAP-38 in the VPAC1 or VPAC2 knockouts appears to reflect only partial inhibition of PACAP signaling, since each of those knockout strains receiving PACAP showed more hypersensitivity than control animals receiving saline did.

All in all, the results raise questions about the best way to target the PACAP system for migraine treatment, as the researchers concluded: “The present study assessed the role of three PACAP receptors in a single in vivo mechanistic migraine mouse model. The findings suggest that VPAC1 and VPAC2 receptors may both be involved in mediating migraine-relevant pain. Therefore, solely targeting specific PACAP receptors might not be effective for migraine treatment, whereas focusing on the circulating PACAP ligand, mast cells, or circulating VIP [vasoactive intestinal peptide; PACAP shares a receptor with VIP] may offer more promising targets for migraine therapy.”

Differential effects of atogepant on trigeminovascular neurons
The focus of work from Rami Burstein (Beth Israel Deaconess Medical Center and Harvard Medical School) and colleagues was to advance understanding of the effects of atogepant, a CGRP receptor antagonist, at the neuronal level, in a study using male rats. The group used cortical spreading depression to activate and sensitize different classes of nociceptive neurons, and then saw what effect atogepant had on the cells.

They found that the drug prevented the activation and sensitization of high-threshold neurons in the spinal trigeminal nucleus (STN). But in another population of nociceptive neurons in the STN, called wide dynamic range (WDR) neurons, while atogepant could not prevent their activation, it did prevent their sensitization.

The findings provide interesting food for thought regarding the effects of atogepant versus other drugs that target the CGRP system, such as the anti-CGRP monoclonal antibody fremanezumab, as the authors wrote:

“One of the more intriguing findings of the current study was that atogepant was able to prevent the sensitization of WDR neurons and attenuate their response magnitude. It is intriguing because it is the first documented mechanistic difference between the effects of fremanezumab on central trigeminovascular (in this case, WDR) [neuronal] responses to [cortical spreading depression] and the effects of atogepant. The translatability of these differences to clinical practice, however, is unclear as currently available published data on comparable effectiveness are lacking.”

An important paper – with relevance to migraine – from the pain field
The brain circuits underlying placebo analgesia have remained mysterious – until now. A team led by Grégory Scherrer, a pain researcher at the University of North Carolina at Chapel Hill, US, recently reported the discovery of a pathway, from the cortex to the pontine nucleus (a brainstem structure) to the cerebellum, underlying placebo pain relief.

This mouse study, published in the journal Nature and covered in MSC news, has received substantial attention, and for good reason. As pain researcher Jeffrey Mogil (McGill University, Montreal, Canada) wrote in an accompanying News & Views: The authors “have certainly delivered the most in-depth neural explanation of placebo analgesia so far, using essentially all of the modern, high-resolution techniques currently available for defining neural circuits in mice.”

The results have import for the migraine field, too, considering that placebo effects have previously been described in migraine. As the outside source for our news story, Luana Colloca, a researcher who investigates the neurobiology of placebo analgesia at the University of Maryland, Baltimore, US, told MSC in an interview: “The study could help us understand why some people do or don’t respond to placebo. This information could be used for treatment or even prevention of migraine attacks,” she said.

Colloca added that perhaps placebo effects could be harnessed not only to improve headache pain but also non-headache symptoms, too.

Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative. Follow him on X (formerly Twitter) @NeilAndrews

Correction: In the discussion of the study of PACAP receptors, due to an editorial error, the original version stated that PACAP was injected into the hind paw, but it was in fact injected systemically. The text has been corrected.

Image credit: 123RF Stock Photo.