Migraine Nerve Cells Send Branches to Both Brain Coverings and Face, With CGRP and Oxytocin Receptors | Research

The takeaway

Some trigeminal ganglion neurons simultaneously project to both the meninges and the face, with these bifurcated cells expressing CGRP and oxytocin receptors — explaining how meningeal and facial pain connect in migraine.

CGRP + OTR co-expressed
Bifurcated trigeminal neurons projecting to both meninges and face co-express CGRP and oxytocin receptors, suggesting oxytocin could modulate migraine pain at the same neural sites targeted by anti-CGRP drugs

What the researchers found

Retrograde tracing in rats confirmed that some trigeminal ganglion (TG) cells send bifurcated projections through both V1 (meningeal/ophthalmic) and V2 (infraorbital/facial) branches. Triple-labeling showed some of these dual-projecting cells expressed both CGRP and oxytocin receptors (OTR). At the meningeal level, OTR was expressed perivascularly and on CGRPergic nerve fibers, suggesting oxytocin could modulate CGRP release at the meningeal vasculature — a key site of migraine pain generation.

Why it matters

Understanding that single nerve cells can relay pain signals from both the brain's covering and the face explains why migraine involves both headache and facial pain/sensitivity. The co-expression of CGRP and oxytocin receptors on these cells suggests oxytocin-based therapies could target the same neurons that CGRP drugs target — potentially offering an additional or complementary approach to migraine treatment.

How the study worked

Male Wistar rats received retrograde neural tracers: True-blue (TB) into the V1 meningeal branch and Fluoro-Gold (FG) into the V2 infraorbital nerve. Immunofluorescence assays identified TG cells triple-labeled with CGRP/FG/TB and OTR/FG/TB. Additional immunofluorescence characterized OTR expression in meningeal vasculature and its relationship to CGRP fibers.

What this study cannot tell us

The study was conducted in rats, and the trigeminal anatomy may differ in humans. The functional significance of the bifurcated projections and OTR expression was not tested — the study is purely anatomical/descriptive. Whether oxytocin actually modulates CGRP release at the meningeal vasculature in vivo was not demonstrated. Only male rats were used, despite migraine being more common in females.

How to read the evidence

This is a basic anatomy study using retrograde tracing and immunofluorescence in rats. It provides novel anatomical evidence but no functional data on whether oxytocin actually modulates CGRP signaling or migraine pain in these circuits.

When this study was published

Published in 2025 in The Journal of Headache and Pain, this study contributes contemporary anatomical evidence to the growing understanding of neuropeptide interactions in migraine.

The bigger picture

This study bridges two important peptide systems in migraine: CGRP (the established target of anti-migraine antibodies) and oxytocin (an emerging analgesic peptide). The anatomical co-localization of CGRP and oxytocin receptors on the same migraine-relevant neurons suggests these neuropeptide systems interact at a fundamental level. As anti-CGRP therapies don't work for all patients, oxytocin-based approaches could offer an alternative mechanism for those who don't respond.

Questions still open

Could intranasal oxytocin reduce migraine pain by activating OTRs on CGRP-containing trigeminal neurons?
Do anti-CGRP antibodies affect oxytocin receptor expression or signaling in the trigeminovascular system?
Are the bifurcated TG neurons more common in individuals prone to migraine with facial allodynia?

Common questions

Why do migraine headaches sometimes cause face pain too?

This study shows that some nerve cells in the trigeminal ganglion (the brain's facial sensation center) send branches to both the brain's covering (meninges, where headache pain originates) and the face simultaneously. When these dual-projecting cells are activated during a migraine, they can transmit pain signals from both locations at once.

Could oxytocin help treat migraine?

This study found oxytocin receptors on the same nerve cells and blood vessels involved in CGRP-mediated migraine pain. Since oxytocin is known to reduce pain signaling, activating these receptors could potentially suppress migraine at the same sites where anti-CGRP drugs work. Intranasal oxytocin is being explored as a potential migraine treatment.

Read the original research

Bifurcated projections from the trigeminal ganglion cells to the transverse sinus and infraorbital nerve in the rat: correlation with the oxytocin receptor and CGRP.

The journal of headache and pain, 26(1), 212

View on PubMed ↗Publisher’s paper ↗

Citation

Martínez-Lorenzana, Guadalupe; Córdova-Quiroga, Aketzalli; Condés-Lara, Miguel; González-Hernández, Abimael. (2025). Bifurcated projections from the trigeminal ganglion cells to the transverse sinus and infraorbital nerve in the rat: correlation with the oxytocin receptor and CGRP.. The journal of headache and pain, 26(1), 212. https://doi.org/10.1186/s10194-025-02186-x