Protein kinase A is involved in neuropathic pain by activating the p38MAPK pathway to mediate spinal cord cell apoptosis

Abstract Background: Neuropathic pain is a serious clinical problem to be solved. Protein kinase A (PKA) is widely distributed in the central nervous system and participates in various signal transduction pathways to regulate cell proliferation and apoptosis. However, it is unclear whether PKA is involved in neuropathic pain. This study aimed to investigate PKA expression in neuropathic pain and its possible mechanisms of involvement. Methods: The mRNA expression dataset of neuropathic pain (GSE24982) was downloaded from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) were screened using the R software. DEGs were subjected to Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. A protein-protein interaction network was constructed using the STRING database, and the Cytoscape plug-in cytoHubba was used to screen for hub genes. A spared nerve injury (SNI) rat model was established and the paw withdrawal threshold was determined using von Frey filaments. Western blotting and immunofluorescence were used to detect the expression and cellular localization of key proteins in the spinal cord, respectively. Western blotting, ELISA, and TUNEL assays were used to detect cell signal transduction, inflammation, and apoptosis, respectively. Results: Among 449 DEGs and 20 hub genes, PKA was identified as a key gene involved in neuropathic pain. After SNI, mechanical allodynia occurred, PKA expression in the spinal cord increased, the p38MAPK pathway was activated, and spinal cord inflammation and apoptosis occurred in rats. Immunofluorescence staining showed that PKA colocalized with neurons, astrocytes, and microglia, and TUNEL with GFAP, Iba-1, Neun double labeling showed that apoptotic cells were mainly neurons. Intrathecal injection of a PKA inhibitor not only relieved mechanical hyperalgesia, inflammatory reaction, and apoptosis in SNI rats, but also inhibited p38MAPK pathway activation. Intrathecal injection of a p38MAPK inhibitor attenuated mechanical hyperalgesia, inflammatory reaction, and apoptosis, but did not affect PKA expression. Conclusions: PKA is involved in neuropathic pain by activating the p38MAPK pathway to mediate spinal cord cell apoptosis. This study provides novel insights that my aid in the elucidation of the pathogenesis of neuropathic pain.