New research into the biological mechanisms of migraine is pointing toward a fresh set of drug targets, offering potential relief for the estimated one-third of the more than 1 billion people worldwide with the condition who do not respond to existing treatments.
Revisiting a Dismissed Pathway
At the center of the new work is substance P, a neuropeptide released by the trigeminal nerve. Substance P drives pain by dilating blood vessels, causing inflammation in the meninges, and amplifying pain signals through the nervous system. Researchers led by Messoud Ashina at the University of Copenhagen found that infusing substance P into people who experience migraines produced effects comparable to those seen in non-sufferers, supporting its direct involvement in the condition.
This matters because substance P was effectively abandoned as a migraine target in the late 1990s after five experimental drugs failed to outperform placebo. For decades, that outcome buried the line of inquiry.
Ashina’s team now believes those trials failed for a specific reason: the drugs only blocked one of substance P’s receptors, the neurokinin-1 receptor (NK1-R). Research since then has identified a second receptor set, the MRGPRX2 receptors, which drive inflammation and act directly on sensory neurons to intensify pain. None of the original drugs touched that pathway.
Michael Moskowitz at Harvard, who first established the trigeminal nerve’s role in migraine, said the earlier failures were never properly interrogated. “After the NK1 receptor-targeted drug trials failed, there were no serious efforts to explain the failure,” he said. “They probably missed blocking the wide range of substance P effects. With new knowledge comes new treatment possibilities.”
A Third Neuropeptide Enters the Picture
Substance P is not the only neuropeptide drawing renewed attention. A third molecule, pituitary adenylate cyclase-activating polypeptide (PACAP), is now under active clinical investigation. Danish pharmaceutical company Lundbeck announced early results this month from a randomised controlled trial of its anti-PACAP monoclonal antibody, bocunebart, reporting that infusions significantly reduced monthly migraine days compared with placebo. Full data is expected at an upcoming conference.
Lars Edvinsson of Lund University in Sweden, who contributed to discovering PACAP’s role in migraine, welcomed the news with measured optimism. “It’s good news, of course, as long as we have hard data,” he said.
Monoclonal antibodies are considered well-suited for this next generation of targets. The approach is already proven: drugs targeting calcitonin gene-related peptide (CGRP), another migraine-linked neuropeptide, have been the most effective migraine therapies since the first CGRP inhibitor received US approval in 2018, roughly halving monthly migraine days and shortening the duration of remaining attacks.
The Limits of Current Treatments
CGRP drugs fail in up to 40 percent of patients. That gap is what motivates the push toward substance P and PACAP as complementary targets.
“CGRP drugs work very well for some people, but they don’t work for everybody,” said Peter Goadsby at King’s College Hospital in London.
The emerging picture suggests migraine is driven by multiple neuropeptide pathways operating in parallel, and that blocking only one of them leaves a substantial proportion of patients without adequate relief. Broadening the target set, rather than optimizing a single pathway, looks increasingly like the direction the field is moving.
Photo by Rick Rothenberg on Unsplash
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