Migraine Basic Science Update: Targets, Antagonists, and More

A wide range of animal studies during the first half of 2025 point to promising new directions for the field.

Editor’s note: This is Migraine Science Collaborative’s latest update on basic science findings of significant import for the migraine field. The studies described below all appeared in the first half of 2025.

A new target for migraine treatment?
The headache field is looking to build upon its success with anti-calcitonin gene-related peptide (CGRP) therapies for migraine. One contender now in clinical development by AstraZeneca is a humanized monoclonal antibody against protease-activated receptor 2 (PAR2), called MEDI0618 (see here and here). PAR2 is a G protein-coupled receptor present in a variety of cell types, including meningeal neurons, mast cells, endothelial cells, and fibroblasts. A recent study published in Brain tested the antibody in a number of preclinical migraine models, firming up the rationale for this new approach to migraine therapy.

The authors injected mice with subcutaneous MEDI0618 before giving the animals different compounds that cause migraine-like pain, to see what effect the antibody might have in various migraine models. The antibody prevented periorbital and hindpaw allodynia in animals that had received a mast cell degranulating compound either systemically or to the dura. The antibody also prevented the decreased rearing behavior that is normally seen in animals that receive the compound; decreased rearing is considered a measure of spontaneous migraine-like headache behavior.

MEDI0618 also had beneficial effects on pain in models of migraine induced by umbellulone (UMB, a compound from the California bay laurel tree, known as the “headache tree”), nitroglycerin, a cocktail of inflammatory mediators, and CGRP. Notably, MEDI0618 also prevented pain from the inflammatory cocktail in mice treated with olcegepant (a small-molecule CGRP receptor antagonist), thus showing that the antibody can work on migraine pain mechanisms that are independent of CGRP.

Finally, the antibody did not prevent headache-like behaviors in a model of post-traumatic headache caused by mild traumatic brain injury, showing the specificity of MEDI0618 to alleviate migraine.

That the antibody was effective in multiple preclinical models makes it a promising approach, according to the study authors.

“PAR2 blockade may therefore offer a broader therapeutic strategy for migraine prevention, potentially providing therapeutic benefit against both CGRP-dependent and CGRP-independent mechanisms of migraine initiation,” they wrote.

“MEDI0618, which has been shown to be safe and well-tolerated in healthy volunteer phase I clinical trials, could be an advantageous therapeutic strategy for migraine prevention in both CGRP responders and non-responders. In addition, clinical studies with MEDI0618 in migraineurs will for the first time test whether blockade of PAR2 can effectively prevent migraine,” according to the authors.

An antagonist that can multitask
Recent research indicates that the pituitary adenylate cyclase-activating polypeptide (PACAP) system and the CGRP system are to a large degree distinct from one another. A new study from researchers in New Zealand now reports the development of multi-receptor antagonists that target both PACAP and CGRP at the same time.

To generate the antagonists, the researchers covalently linked CGRP8-37 to PACAP6-38 (which are truncated forms of CGRP and PACAP, respectively) at different amino acids of these peptides. The question was whether the antagonists could inhibit the activity of CGRP by targeting the CGRP and amylin 1 receptor, or inhibit PACAP activity via targeting of PAC1, VPAC1, and VPAC2 – the three receptors for PACAP.

The investigators used a cell line transfected with the antagonists, as well as rat spinal cord cultures that endogenously express the receptors. In both systems, the new compounds successfully antagonized the signaling of the CGRP- and PACAP-responsive receptors. To show this, the researchers measured the effects of the antagonists on levels of cyclic AMP, an intracellular signaling molecule whose accumulation is stimulated by CGRP and PACAP.

“This proof-of-concept study,” the authors concluded, “shows that blocking both CGRP- and PACAP-responsive receptor signaling with a single molecule is feasible and may provide scope for developing more efficacious therapies targeting these receptors. Targeting both CGRP and PACAP receptor systems in one molecule could be therapeutically beneficial and offer efficacy for a wider subset of patients with migraine.”

A role for delta-opioid receptors
Another pharmacological study tested whether targeting δ-opioid receptors (DORs) could have beneficial effects on headache. The work, from Amynah Pradhan and colleagues at Washington University School of Medicine in St. Louis, and the University of Illinois at Chicago, US, tested the impact of a DOR agonist (called SNC80) in a mouse model where headache was induced by low doses of acute or chronic PACAP, administered systemically. Effects in a model of headache resulting from CGRP administration were also evaluated.

The key result was that SNC80 reversed the allodynia that had been established by chronic PACAP treatment, in the PACAP headache model (this was also the case in the CGRP model as well). Further, chronic treatment with the drug also prevented PACAP-induced allodynia from developing in the first place.

The investigators also examined the co-expression of DORs with PACAP, or with PAC1, in different regions of the brain associated with migraine. Most notably, three regions of the brain – the somatosensory cortex, hippocampus, and trigeminal nucleus caudalis – showed high co-expression of DORs and PAC1.

Importantly, the investigators also found that chronic PACAP and CGRP worked through different mechanisms to cause allodynia. To wit, olcegepant, a CGRP receptor antagonist, only reduced allodynia in the CGRP model, while a PACAP-PAC1 receptor antagonist had no significant effect on allodynia caused by CGRP.

“These experiments establish a translationally significant mouse model of PACAP-induced headache and suggest that δ-receptors may regulate migraine through modulation of the PACAP-ergic system,” according to the authors.

Advancing understanding of a common comorbidity of migraine
The topic of a recent study in Cephalalgia from Frank Porreca and colleagues at the University of Arizona, Tucson, US, was the comorbidity of migraine with endometriosis, the latter a painful condition characterized by the growth of uterine-like tissue outside of the uterus. Specifically, the group sought underlying mechanisms of this comorbidity by using a mouse model of endometriosis where endometriotic lesions grow in the abdominal cavity. Of particular interest was the role of prolactin, considering that this neurohormone secreted from the anterior pituitary is associated with pain and migraine, particularly in women, and with endometriosis.

The investigators first showed that the endometriosis mice developed abdominal allodynia, compared to control animals, but did not develop cephalic allodynia. However, the mice did show cephalic allodynia when exposed to umbellulone (UMB), indicating that endometriosis can “prime” the trigeminal system to show increased sensitivity to migraine triggers.

Additional experiments pointed to prolactin as a key factor underlying that finding. Specifically, compared to control animals, the endometriosis mice showed increased serum levels of prolactin, as well as increased levels of prolactin receptor isoforms in cultured trigeminal neurons. Those neurons also showed increased excitability in response to UMB, according to electrophysiological experiments that measure different aspects of neuronal activity.

Further experiments continued to build the case for a key role of prolactin. Endometriosis animals treated with cabergoline, a dopamine receptor agonist that inhibits pituitary prolactin, failed to show cephalic allodynia in response to UMB, unlike control mice, which did show this pain-related behavior. Further, in endometriosis animals, cabergoline reduced the expression of prolactin receptor isoforms in trigeminal ganglion neurons. And, trigeminal neurons from endometriosis mice that had been treated with cabergoline showed lower electrical excitability in response to UMB, compared to endometriosis mice that had received a saline control.

“These findings provide avenues for therapy in endometriosis comorbid migraine and other pain conditions, including the use of dopamine D2 receptor agonists and future development of antibodies against prolactin or PRLR [the prolactin receptor],” the authors wrote of the potential clinical implications of their findings.

Immediate implications for clinical trials of cannabis for migraine
A recent basic science study examined the effects of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), using three different preclinical models of migraine (see MSC related news story on the study). The goal was to identify the best combinations of these two main active compounds in cannabis.

The compounds were tested in a CGRP model of migraine, a sodium nitroprusside migraine model, and a cortical spreading depression (CSD) model where light is used to evoke CSD. The results pointed to a 100:1 ratio of CBD to THC as the most effective at dampening migraine-like symptoms in mice.

“This paper will help guide designing clinical trials testing cannabis in migraine patients. It’s a transformative study for studying the effects of cannabinoids in migraine, particularly in understanding effective dosage combinations of CBD to THC,” said Tally Largent-Milnes, a researcher at the University of Arizona, Tucson, US, who spoke to MSC about the paper but was not involved with the work.

The researchers themselves are also excited about the clinical implications of their work.

“The efficacy observed across multiple models, along with emerging clinical data, suggest that CBD and THC could be viable candidates for further investigation in human trials,” said first author Erik Zorrilla, who carried out some of the study’s experiments while he was a PhD student in Andrew Russo’s lab at the University of Iowa.

Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative.

Image credit: 123RF Stock Photo.