# Histamine plasma levels from dietary histidine/histamine intake correlate with CGRP in trigeminal tissues

## TL;DR

High dietary histidine or histamine increases CGRP levels in trigeminal tissues, which may contribute to headaches and migraines.

## Contribution

This study shows that dietary histamine/histidine intake correlates with CGRP levels in trigeminal afferents, linking diet to migraine mechanisms.

## Key findings

- Mice on high histidine/histamine diets had increased CGRP in trigeminal ganglia.
- Capsaicin-stimulated CGRP release from the dura was higher in mice with high histidine/histamine diets.
- The effect was more pronounced in male mice after normalizing for body weight.

## Abstract

Trigeminal afferents innervating the meninges are likely involved in the generation of headaches and migraine. A major proportion of these afferents can release calcitonin gene-related peptide (CGRP) upon stimulation. Several substances, among them histamine, are known to induce headaches and trigger migraine. In addition to endogenous histamine, high dietary intake of histidine or histamine, or impaired histamine degradation in the gut, can lead to symptoms of histamine intolerance such as headache. However, it remains unclear whether and how dietary histamine impacts the trigeminal system, particularly trigeminal afferents releasing CGRP.

In mice supplied with high dietary histidine/histamine, CGRP content in different tissues and CGRP release from the dura mater was utilized as a measure of potential histamine-induced sensitization of trigeminal afferents. After 19–32 days of feeding mice with a diet containing high histidine and histamine levels, CGRP concentrations were measured in plasma as well as in homogenized samples of ileum, trigeminal ganglia, spinal medulla and cerebellum, and compared with those from a control group fed a standard chow. CGRP content and release data were correlated with previously analysed histamine content and release data. Likewise, CGRP release from the cranial dura mater stimulated with the TRPV1 receptor agonist capsaicin was determined using our validated hemisected cranial preparation.

Mice fed high histamine-histidine diets exhibited an increased trigeminal ganglion CGRP concentration that correlated with diet-derived plasma histamine levels. The capsaicin stimulated CGRP release from the dura mater was higher in animals supplied with high histidine/histamine diet compared to control animals. An exponentially higher amount of dietary histidine likely converted into histamine in the gut appeared to be the main contributor to modulating CGRP levels. Separating for sexes and normalizing to the body weight of the animals, this difference was attributable to male mice.

High dietary histidine or histamine, by elevating plasma histamine levels, cause increased CGRP concentrations and ongoing CGRP release from peptidergic afferents in trigeminal tissues. Exogenous histamine-induced sensitization of trigeminal afferents may facilitate headache generation and contribute to trigger migraine attacks.

The online version contains supplementary material available at 10.1186/s10194-025-02178-x.