Neuropeptide VIP Excites Female-Specific Trigeminal Neurons Via VPAC1, Offering Clues to Why Migraines Are More Common in Women

What the researchers found

In isolated female rat trigeminal ganglion Ah-type neurons:

- VIP (100 nM) significantly increased firing frequency of repetitive discharge

- VIP narrowed action potentials and increased down-stroke velocity

- VIP deepened after-hyperpolarization (AHP)

- AP and repolarization changes were reversed by Iberiotoxin (BK channel blocker), except AHP which was abolished by Apamin (SK channel blocker)

- All VIP-mediated increases in firing frequency and repolarization changes were completely blocked by PG97-269 (VPAC1 antagonist)

- PG-99-465 (VPAC2 antagonist) had no effect

- PG97-269 alone slightly but significantly reduced baseline firing

- Conclusion: VIP excites female-specific Ah-type neurons via VPAC1, which also plays a minor role in basal neuroexcitation

Why it matters

Migraine affects about 1 billion people worldwide, with women affected 3 times more than men. Understanding why requires identifying sex-specific neural mechanisms. This study reveals that VIP activates a female-specific neuron subtype in the trigeminal system through VPAC1, providing a molecular explanation for sex-based differences in migraine susceptibility and potentially a new drug target.

How the study worked

Trigeminal ganglion neurons were isolated from adult female rats. Myelinated Ah-type neurons were identified and action potentials were recorded before and after VIP treatment using whole-cell patch-clamp technique. VPAC1 (PG97-269) and VPAC2 (PG-99-465) receptor antagonists, Iberiotoxin (BK channel blocker), and Apamin (SK channel blocker) were used to dissect the signaling mechanisms.

What this study cannot tell us

This was an in vitro electrophysiology study using isolated rat neurons, which may not fully represent human trigeminal physiology. The Ah-type neuron is characterized as female-specific in rats, but this finding needs validation in human tissue. VIP's role in the complex migraine pathophysiology involves multiple cell types and brain regions not captured in isolated neuron recordings. The concentrations used (100 nM) may not reflect physiological VIP levels during migraine attacks.

How to read the evidence

This is a basic science electrophysiology study using isolated rat neurons. While it provides precise mechanistic data, it is far from clinical application and requires validation in human tissue and in vivo models.

When this study was published

Published in 2026, this is very recent research advancing the understanding of VIP's role in sex-specific migraine mechanisms.

The bigger picture

While anti-CGRP antibodies have transformed migraine treatment, VIP represents another neuropeptide pathway involved in migraine that is less well understood. VIP levels rise during migraine attacks, and this study shows how it excites specific trigeminal neurons. Understanding VIP's role alongside CGRP could lead to combination therapies or alternative treatments for patients who don't respond to anti-CGRP drugs.

Questions still open

• Could VPAC1 receptor antagonists serve as a new class of migraine preventive treatment, particularly for women?
• How does VIP-mediated trigeminal excitation interact with CGRP signaling in the migraine cascade?
• Do Ah-type neurons exist in human female trigeminal ganglia with similar VIP sensitivity?

Common questions

Read the original research

Effects of vasoactive intestinal peptide on neuroexcitability of female-specific subpopulation of myelinated Ah-type neurons isolated from trigeminal ganglia of adult female rats.

Neuropeptides, 115, 102569

Citation

Yan, Feng; Zhong-Xuan, Pan; Li-Li, Tan; Luo, Fang; Hai-Ying, Ding. (2026). Effects of vasoactive intestinal peptide on neuroexcitability of female-specific subpopulation of myelinated Ah-type neurons isolated from trigeminal ganglia of adult female rats.. Neuropeptides, 115, 102569. https://doi.org/10.1016/j.npep.2025.102569