Researchers are revisiting substance P, a neuropeptide linked to migraine pain, after it was dismissed as a treatment target 25 years ago. A recent study shows it causes headaches and blood vessel dilation in both migraine sufferers and others, suggesting potential for new therapies. This comes amid advances in blocking other migraine-related peptides like CGRP and PACAP.
Migraine affects more than 1 billion people worldwide, with one in three not responding to existing treatments. Substance P, released by the trigeminal nerve, plays a role by dilating blood vessels, inflaming the meninges around the brain, and amplifying pain signals in the nervous system.
Messoud Ashina at the University of Copenhagen and colleagues conducted a placebo-controlled study on substance P. Last year, they found that infusing it caused headaches in 71 percent of people without migraines, along with dilation of the superficial temporal artery. Their latest work shows a similar effect in those who experience migraines, reinforcing substance P's involvement.
In the late 1990s, five experimental drugs targeting substance P failed to outperform placebos, leading to its abandonment. Those drugs focused solely on the neurokinin-1 receptor (NK1-R), but substance P also binds to MRGPRX2 receptors, which trigger inflammation, and directly affects sensory neurons to heighten pain.
"After the NK1 receptor–targeted drug trials failed, there were no serious efforts to explain the failure," says Michael Moskowitz at Harvard, who helped uncover the trigeminal nerve's role in migraine. "With new knowledge comes new treatment possibilities, and based on new and existing knowledge, it seems timely and prudent to revisit strategies that target substance P."
Monoclonal antibodies, successful against calcitonin gene-related peptide (CGRP) since its first approval in 2018, offer a direct way to block such molecules. These CGRP inhibitors have halved monthly migraine days for many but fail for up to 40 percent of patients.
Meanwhile, Lundbeck reported early trial results for its anti-PACAP antibody bocunebart, showing reduced monthly migraine days versus placebo. Full data is expected at an upcoming conference. "It’s good news, of course, as long as we have hard data," says Lars Edvinsson of Lund University, involved in discovering PACAP and substance P's roles.
"CGRP drugs work very well for some people, but they don’t work for everybody," notes Peter Goadsby at King’s College Hospital in London, who co-discovered CGRP's role in the 1990s. "Finding the next thing that will benefit the hundreds of millions of people who are not well treated by current therapies remains an important challenge."
Moskowitz suggests optimism, as substance P, CGRP, and PACAP act on meningeal vessels differently, and combining blocks could help non-responders. However, Edvinsson views them as supplementary: "I don’t think [these targets] will replace CGRP. I think they are more like the sprinkles on top of the ice cream."
