Altered aminoacid and lipid metabolism in a rat orofacial inflammation model determined by omics approach: potential role in trigeminal sensitisation

TL;DR

This study uses omics methods to identify metabolic and genetic changes in a rat model of orofacial inflammation, revealing potential targets for treating trigeminal pain and headaches.

Contribution

The study integrates metabolomic and transcriptomic data to uncover novel mechanisms in trigeminal sensitization linked to orofacial pain.

Findings

Plasma levels of carnosine, serotonin, and fatty acids increased, while amino acids and lipids like tryptophan and sphingolipids decreased.

CFA altered gene expression in the trigeminal ganglia, upregulating Cxcr3 and downregulating GNRHR.

Altered amino acid metabolism and fatty acid oxidation were linked to neuroinflammation and immune responses.

Abstract

Trigeminal activation and sensitisation involved in chronic inflammatory orofacial pain share several similarities with headaches, including migraine. Therefore, understanding the pathophysiological mechanisms is important to determine novel therapies, in which animal models are crucial. Here we aimed to identify key mediators, mechanisms and networks using unbiased multi-omic approaches in a rat orofacial inflammatory pain model.

Complete Freund’s Adjuvant (CFA, 50 µl, 1 mg/mL) was injected into the right whisker pad of male Wistar rats (n = 5–11/group), mechanonociceptive threshold was measured by von Frey filaments. Plasma concentrations of metabolites were measured both by targeted (MxP Quant 500 kit) and untargeted mass spectrometry methods on day 3 when maximal facial allodynia developed. Next-generation sequencing of the trigeminal ganglia (TG) was performed, furthermore, transcriptomic and plasma metabolomic data were analysed together.

Plasma carnosine, serotonin and fatty acid levels significantly increased, while tryptophan, kynurenine, tyrosine, phenylalanine, asparagine, glycerolipids, and sphingolipids decreased in response to orofacial inflammation. CFA upregulated the Cxcr3 chemokine receptor and downregulated GNRHR in the TG. Bioinformatic analysis revealed altered amino acid metabolism and fatty acid beta-oxidation involved in mitochondrial energy production, neuroinflammation and immune responses.

Integrated joint pathway analysis of metabolomic and transcriptomic data provides a useful approach to determine pathophysiological mechanisms of trigeminal sensitization and identify novel drug targets for orofacial pain and headaches.

The online version contains supplementary material available at 10.1186/s10194-025-02024-0.

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