New Ion Channel TRPM3 Triggers Release of the Migraine Peptide CGRP From Nerve Cells | Research

The takeaway

Activating the TRPM3 ion channel in trigeminal nerve cells triggers release of CGRP — the key migraine peptide — and causes blood vessel dilation, with possible sex differences suggesting enhanced release in female tissue.

TRPM3-CGRP colocalization confirmed
The TRPM3 channel and CGRP peptide were found together in the same trigeminal neurons — connecting a new ion channel to the central migraine pathway

What the researchers found

TRPM3 activation with the agonist CIM0216 (100 μM) triggered CGRP release from trigeminal ganglia, with indications of enhanced release in female tissues. Immunohistochemistry confirmed that TRPM3 and CGRP colocalize in trigeminal ganglion neurons, and TRPM3 was also detected in cerebral and meningeal arterial structures.

CIM0216 application increased cytosolic calcium in CGRP-expressing trigeminal neurons in transgenic mice. However, subcutaneous CIM0216 did not induce allodynia-like symptoms in rats, suggesting TRPM3 activation alone may be insufficient to produce migraine-like pain behavior in vivo despite triggering CGRP release ex vivo.

Why it matters

Current migraine treatments target CGRP after it's already released. Identifying what triggers CGRP release upstream — in this case, the TRPM3 channel — opens the door to preventing CGRP release in the first place rather than just blocking its effects. TRPM3 could become a new drug target for migraine prevention, potentially complementing existing CGRP-targeting therapies.

How the study worked

Multi-modal preclinical study using male and female Sprague-Dawley rats and transgenic female mice. CGRP release from trigeminal ganglia and dura mater was measured by ELISA after CIM0216 stimulation. Myograph studies assessed vasodilation in cerebral and meningeal arteries. Immunohistochemistry examined TRPM3/CGRP colocalization in rat and human tissue. Mechanical sensitivity tests assessed behavioral responses. Calcium imaging was performed in transgenic mouse CGRP neurons.

What this study cannot tell us

The TRPM3 agonist CIM0216 triggered CGRP release ex vivo but did not produce migraine-like pain behavior in vivo, raising questions about the physiological relevance of TRPM3 activation alone. The sex difference in CGRP release was indicated but not conclusively established. The study did not identify endogenous TRPM3 activators relevant to migraine triggers. Human dura mater was examined for expression but not for functional CGRP release.

How to read the evidence

This is a preclinical study using multiple complementary techniques (ELISA, myography, immunohistochemistry, calcium imaging, behavioral testing) in rats, mice, and human tissue. While the multi-modal approach strengthens the findings, the disconnect between ex vivo CGRP release and absence of in vivo pain behavior limits the translational implications.

When this study was published

Published in 2026, this is a very recent study contributing to the expanding understanding of upstream mechanisms that trigger CGRP release in migraine.

The bigger picture

The migraine field has been transformed by CGRP-targeting therapies, but understanding what triggers CGRP release in the first place remains an active frontier. TRPM3 joins other TRP channels (TRPV1, TRPA1) as upstream activators of the migraine cascade. The sex difference observed — enhanced CGRP release in female tissue — is particularly noteworthy given that migraine affects women three times more often than men, and may contribute to explaining this disparity.

Questions still open

What endogenous molecules activate TRPM3 in the trigeminal system during migraine attacks?
Could TRPM3 antagonists prevent CGRP release and serve as a new class of migraine preventive therapy?
Does the enhanced CGRP release in female trigeminal tissue contribute to the female predominance of migraine?

Common questions

What is CGRP and why is it so important in migraine?

CGRP (calcitonin gene-related peptide) is a small protein released by trigeminal nerve cells during migraine attacks. It causes blood vessels in the brain to dilate and triggers inflammation and pain signaling. CGRP is so central to migraine that blocking it — with antibodies like erenumab or small molecules like rimegepant — has become one of the most successful approaches to migraine treatment in decades.

Why might TRPM3 explain why women get more migraines?

This study found indications that activating TRPM3 caused more CGRP release from female trigeminal tissue than from male tissue. Since CGRP is the key driver of migraine, this sex difference in release could help explain why women experience migraines roughly three times more often than men. If confirmed, this could lead to sex-specific treatment approaches.

Read the original research

TRPM3 activation causes CGRP release in trigeminal neurons: Implications for migraine mechanisms.

Headache, 66(3), 672-687

View on PubMed ↗Publisher’s paper ↗

Citation

Reducha, Philip V; Nielsen, Lukas K S; Jensen, Mette N; Edvinsson, Jacob C A; Kazantzi, Spyridoula; Wæver, Sofia L; Lylloff, Tanja; Westgate, Connar S J; Edvinsson, Lars; Haanes, Kristian A. (2026). TRPM3 activation causes CGRP release in trigeminal neurons: Implications for migraine mechanisms.. Headache, 66(3), 672-687. https://doi.org/10.1111/head.15082