Puerarin Improves Cancer-Induced Bone Pain by Recovering Mitochondrial Dysfunction in the Spinal Cord

Cancer metastases induce bone pain and central sensitization in the spinal cord. Mitochondrial dysfunction is associated with pian signal transmission and involved in cancer-induced bone pain. Pueratin (Pue) is a natural isoflavone compound that works as a potential natural neuroprotective agent. However, the mechanisms of Pue on cancer pain remain unclear. In this study, a cancer-induced bone pain (CIBP) rat model was established and Pue was administered intrathecally. As a result, CIBP model rats exhibited as the evoked mechanical pain, thermal pain, and spontaneous pain, the elevated neurological damage and mitochondrial dysfunction in the spinal cord. Pue administration improved pain related behaviors, decreased the neuronal activity, reduced NLRP3 inflammasome-mediated inflammation, and elevated mitochondrial dysfunction in the spinal cords of CIBP rats. Proteomical data showed that in the spinal synaptosomes, 59 differentially expressed proteins (DEPs) were significantly up-regulated while 128 DEPs were down-regulated. Among them, 5 genes were found to be overlapped for CIBP and Pue-potential targets and Src was belonged to the hub genes. Database analysis and experimental assay showed that Pue bound with Src at the affinity of 7.9 ± 0.2 µM, and decreased Src level and phosphorylation in the spinal cord of CIBP rats and in primary astrocytic cells. In addition, Pue also recovered levels of mitochondrial membrane potential and reactive oxygen species, and decreased inflammation in primary astrocytic cells. To summarize, Pue inhibits spinal Src activity, restores mitochondrial function, reduces central sensitization in the spinal cord, and relieves cancer-induced bone pain. This study may provide a basis for the application of Pue on the relief of cancer pain.