https://doi.org/10.4081/cc.2026.15931
Trigeminal ganglion neurons lack detectable GLP-1 receptor expression: a cross-species single-cell transcriptomic study
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Accepted: 25 September 2026
Published: 16 October 2026
Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are accumulating signals of potential benefit in headache disorders, but the cellular locus of any anti-cephalalgic action is unknown. A direct effect on the trigeminovascular system would require GLP1R to be expressed by cells of the trigeminal ganglion (TG), and we therefore investigated whether GLP1R is expressed by TG neurons or non-neuronal cells.
Methods: We reanalysed public single-cell/single-nucleus transcriptomic data from mouse and human TG, quantifying GLP1R detection per cell type with exact binomial 95% confidence intervals (CIs). GLP1R and the second incretin receptor GIPR were benchmarked against validated G protein-coupled receptor (GPCR) drug targets and nociceptor markers, and GLP1R detection was verified in pancreatic islets, where it is expressed.
Results: GLP1R was detected in 0.09% of mouse and 0.05% of human trigeminal neurons, whereas validated GPCR drug targets were robustly detected in the same cells. GLP1R was undetected in the peptidergic subtype and ≤0.17% across the other mouse neuronal subtypes, was at the limit of detection in human neurons, and was at or below the limit of detection in all human non-neuronal compartments, while GPCRs and compartment markers labelled their expected populations. The same pipeline detected GLP1R in pancreatic beta cells, confirming assay sensitivity.
Conclusions: Across both mouse and human TG, GLP1R transcripts were not detectably expressed by neurons or non-neuronal cells. The anti-headache signals of GLP-1 RAs are therefore unlikely to be initiated by GLP1R within TG cell bodies and more plausibly reflect extraganglionic mechanisms.
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