This study investigated the impact of lidocaine-induced neurotoxicity on microRNA (miRNA) expression in the spinal cord of rats. Sprague–Dawley rats underwent intrathecal catheterization and were randomly assigned to receive either 10% lidocaine or normal saline for three consecutive days. Post-treatment, the paw withdrawal threshold significantly increased, accompanied by notable histopathological changes. Additionally, 470 miRNAs exhibited altered expression following lidocaine treatment, with miR-155-5p, miR-3544, and miR-675-5p showing significant changes. Gene Ontology analysis identified cellular metabolic processes as the most significantly enriched functions. Kyoto encyclopedia of genes and genomes pathway analysis revealed that the enriched signaling pathways are associated with neural injury and neuroprotection, and are involved in regulating cellular metabolism. The Mitogen-Activated Protein Kinase (MAPK) signaling pathway was notably enriched, with Mitogen-activated protein kinase kinase kinase 10 (Map3k10) and Mitogen-activated protein kinase kinase kinase 14 (Map3k14) identified as target genes of miR-155-5p. Following lidocaine treatment, there was an observed increase in the expression of MAP3K10 and MAP3K14 at both the mRNA and protein levels. These results indicate that miR-155-5p, miR-3544, and miR-675-5p might be significantly involved in lidocaine-induced neurotoxicity by influencing cellular metabolism. Furthermore, miR-155-5p/MAPK shows potential therapeutic value for treating lidocaine-induced neurotoxicity.
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