Neuronal GLUT3 alleviates hyperalgesia and neuroinflammation in chronic migraine mice via the TCA cycle

Background 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. Methods Plasma samples from CM 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 filaments and hot plate tests. 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 and intervention with 20 mg/kg 3-nitropropionic acid (3-NPA), a tricarboxylic acid (TCA) cycle inhibitor, were performed to verify the regulatory loop’s specificity and clinical therapeutic potential, as well as 100 mg/kg Idebenone. Results Patients with CM 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 enhanced TCA cycle function, increased mechanical pain thresholds, and inhibited central sensitization by downregulating 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. 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. Conclusions These results identify the neuronal GLUT3-TCA cycle-NF-κB axis as a key regulatory pathway in CM, bridging metabolic dysfunction and neuroinflammation. Notably, the clinically available mitochondrial protective agent Idebenone mimics these benefits via TCA cycle targeting, underscoring its application potential in the cilinic. These findings offer novel mechanistic insights and metabolic-targeted therapeutic strategies for CM.