Neuronal GLUT3 alleviates hyperalgesia and neuroinflammation in chronic migraine mice

Chronic migraine (CM) is closely linked to systemic metabolic disorders and neuroinflammation, but the molecular mechanisms connecting energy metabolism dysfunction to pain-related inflammation remain unclear. Plasma samples from migraine patients were analyzed using transcriptomics and metabolomics. A CM mouse model was induced by administration of nitroglycerin (NTG). Behavioral evaluations were conducted using von Frey filament testing. Western blotting, immunofluorescence, transcriptome, targeted metabolomics techniques were employed to investigate the molecular mechanisms. 18 F-FDG-PET/CT and 2-NBDG staining were employed to assess glucose uptake. Neuron-specific GLUT3 overexpression, 20 mg/kg 3-nitropropionic acid (3-NPA; a succinate dehydrogenase inhibitor used to perturb TCA-cycle function), and 200 mg/kg idebenone were used to evaluate the involvement of mitochondrial metabolism in NTG-induced migraine-like phenotypes. Patients with migraine exhibited energy metabolism abnormalities including dysregulated oxidative phosphorylation pathway-related genes and reduced plasma levels of TCA cycle-related metabolites. NTG-induced mice exhibited decreased glucose uptake in the trigeminal nucleus caudalis (TNC) and neuron-specific GLUT3 downregulation, rather than glial cells. Neuron-specific GLUT3 overexpression restored TCA-cycle-related metabolic alterations, increased mechanical withdrawal thresholds, and reduced the expression of c-Fos and calcitonin gene-related peptide (CGRP), accompanied by an inhibition of NF-κB pathway. Furthermore, 3-NPA reversed the inhibitory effect of neuron-specific GLUT3 overexpression on the NF-κB pathway. Pretreatment with idebenone, a clinically approved mitochondrial protective agent, alleviated CM-related mechanical allodynia and reversed the upregulation of c-Fos/CGRP in the TNC of NTG-induced mice. These findings suggest that neuronal GLUT3-related mitochondrial metabolism is associated with pain-related neuronal activation and inflammatory signaling in the NTG-induced CM model, and highlight GLUT3 and downstream mitochondrial metabolic pathways as potential targets for CM research.