Early molecular alterations in anterior cingulate cortex and hippocampus in a rodent model of neuropathic pain

Neuropathic pain is clinically associated with the development of mental disorders. However, the early molecular changes possibly related to the late-set depressive consequence of neuropathic pain were obscure so far. In this genome-wide study, we aimed to characterize the molecular mechanisms at the early and late stages of neuropathic pain. The genetic data from anterior cingulate cortex (ACC) tissues of neuropathic pain mice in Gene Expression Omnibus database were analyzed by weighted gene co-expression network analysis. Modules with clinical significance were respectively distinguished for mice at two and eight weeks after operation. The genes that co-expressed in modules from two postoperative time points were obtained, and annotated by gene ontology and pathway enrichment analyses. Moreover, the hub genes were identified from the protein-protein interaction network, and their expression levels were validated by molecular biology experiments. Overall, two modules were respectively found to be associated with the neuropathic pain mice with and without depressive consequence. A total of 20 genes co-expressed in both modules, and MAPK signaling pathway was the most significant pathway for these genes. Furtherly, Dusp1, c-Fos and Gadd45β were identified as the hub genes. At two weeks after sciatic nerve cuffing, Gadd45β was significantly downregulated at both mRNA and protein levels in ACC and hippocampus, while the significant upregulation was only observed in mRNA and protein levels for c-Fos in ACC. This study firstly compared the gene expression profiles between neuropathic pain animals with and without depressive-like behavior, and we suggested the early changes in the activities of MAPK signaling pathway, c-Fos and Gadd45β might be related to late-onset depressive behavior induced by peripheral nerve injury.