Neuroinflammation in the medial prefrontal cortex exerts a crucial role in bone cancer pain

Abstract

Bone cancer pain (BCP) is one of the most common types of pain in cancer patients which compromises the patient’s functional status, quality of life, and survival. Central hyperalgesia has increasingly been identified as a crucial factor of BCP, especially in the medial prefrontal cortex (mPFC) which is the main cortical area involved in the process of pain and consequent negative emotion. To explore the genetic changes in the mPFC during BCP occurrence and find possible targets for prediction, we performed transcriptome sequencing of mPFC in the BCP rat model and found a total of 147 differentially expressed mRNAs (DEmRNAs). A protein-protein interaction (PPI) network revealed that the DEmRNAs mainly participate in the inflammatory response. Meanwhile, microglia and astrocytes were activated in the mPFC of BCP rats, further confirming the presence of neuroinflammation. In addition, Gene Ontology (GO) analysis showed that DEmRNAs in the mPFC are mainly involved in antigen processing, presentation of peptide antigen, and immune response, occurring in the MHC protein complex. Besides, the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that DEmRNAs are mainly enriched in the pathways of phagosome, staphylococcus aureus infection, and antigen processing, in which MHCII participate. Furthermore, immunostaining showed that MHCII is mainly located in the microglia. Microglia are believed to be involved in antigen processing, a key cause of BCP. In vivo, minocycline (MC) treatment inhibits the activation of microglia and reduces the expression of MHCII and proinflammatory cytokines, thereby alleviating BCP and pain-related anxiety. Taken together, our study identified differentially expressed genes in the BCP process and demonstrated that the activation of microglia participates in the inflammatory response and antigen process, which may contribute to BCP.

MOTS-c is an effective target for treating cancer-induced bone pain through the induction of AMPK-mediated <?A3B2 pi6?>mitochondrial biogenesis

“…Given that astrocytes and microglia have been recognized as important contributors to the development of BCP [41,42], we also tested whether astrocytes and microglia are involved in the therapeutic effects of MOTS-c. Iba1 and GFAP were used as markers of microglia and astrocyte activity, respectively. As shown in Figure 8A-D, compared with the sham group, the BCP group exhibited a significant increase in iba1-positive microglia (P<0.01 for the sham group vs the BCP group) and GFAP-positive astrocytes (P<0.01 for the sham group vs the BCP group).…”

Microglia Promote Inhibitory Synapse Phagocytosis in the Spinal Cord Dorsal Horn and Modulate Pain-Like Behaviors in a Murine Cancer-Induced Bone Pain Model

“…Microglia will be converted into a reactive state when cancer-induced bone pain occurs and develops. 10 Microglial inhibitor minocycline can significantly relieve bone cancer pain. 11 Taken together, these data imply that microglia make great contributions to cancer pain processing.…”