Esketamine inhibits the c-Jun N-terminal kinase pathway in the spinal dorsal horn to relieve bone cancer pain in rats.

Cancer-induced bone pain (CIBP) is one of the most common and feared symptoms in patients with advanced tumors. The X-C motif chemokine ligand 12 (CXCL12) and the CXCR4 receptor have been associated with glial cell activation in bone cancer pain. Moreover, mitogen-activated protein kinases (MAPKs), as downstream CXCL12/CXCR4 signals, and c-Jun, as activator protein AP-1 components, contribute to the development of various types of pain. However, the specific CIBP mechanisms remain unknown. Esketamine is a non-selective N-methyl-d-aspartic acid receptor (NMDA) inhibitor commonly used as an analgesic in the clinic, but its analgesic mechanism in bone cancer pain remains unclear. We used a tumor cell implantation (TCI) model and explored that CXCL12/CXCR4, p-MAPKs, and p-c-Jun were stably up-regulated in the spinal cord. Immunofluorescence images showed activated microglia in the spinal cord on day 14 after TCI and co-expression of CXCL12/CXCR4, p-MAPKs (p-JNK, p-ERK, p-p38 MAPK), and p-c-Jun in microglia. Intrathecal injection of the CXCR4 inhibitor AMD3100 reduced JNK and c-Jun phosphorylations, and intrathecal injection of the JNK inhibitor SP600125 and esketamine also alleviated TCI-induced pain and reduced the expression of p-JNK and p-c-Jun in microglia. Overall, our data suggest that the CXCL12/CXCR4-JNK-c-Jun signaling pathway of microglia in the spinal cord mediates neuronal sensitization and pain hypersensitivity in cancer-induced bone pain and that esketamine exerts its analgesic effect by inhibiting the JNK-c-Jun pathway.

Integrated Analysis of Omics Data Reveal AP-1 as a Potential Regulation Hub in the Inflammation-Induced Hyperalgesia Rat Model.

Inflammation-associated chronic pain is a global clinical problem, affecting millions of people worldwide. However, the underlying mechanisms that mediate inflammation-associated chronic pain remain unclear. A rat model of cutaneous inflammation induced by Complete Freund's Adjuvant (CFA) has been widely used as an inflammation-induced pain hypersensitivity model. We present the transcriptomics profile of CFA-induced inflammation in the rat dorsal root ganglion (DRG) via an approach that targets gene expression, DNA methylation, and post-transcriptional regulation. We identified 418 differentially expressed mRNAs, 120 differentially expressed microRNAs (miRNAs), and 2,670 differentially methylated regions (DMRs), which were all highly associated with multiple inflammation-related pathways, including nuclear factor kappa B (NF-κB) and interferon (IFN) signaling pathways. An integrated analysis further demonstrated that the activator protein 1 (AP-1) network, which may act as a regulator of the inflammatory response, is regulated at both the transcriptomic and epigenetic levels. We believe our data will not only provide drug screening targets for the treatment of chronic pain and inflammation but will also shed light on the molecular network associated with inflammation-induced hyperalgesia.

Volatile anesthetic sevoflurane suppresses lung cancer cells and miRNA interference in lung cancer cells.

PURPOSE: Sevoflurane is widely used in lung cancer surgery. It is well known that volatile anesthetics have a lung-protective effect in lung cancer surgery. However, the association between the inhibition of cancer cells and miRNAs interference remains unknown. Whether sevoflurane can affect some miRNAs in A549 cells has not been reported. The main aim of the present study was to investigate the effect of 3% sevoflurane on A549 cells and assess whether it regulates A549 cells by interfering with miRNA. METHODS: In three percent sevoflurane-pretreated A549 cells, treated for a duration of 30 minutes, the apoptosis rate of A549 cells was evaluated using a flow cytometer. The expression of 6 types of miRNAs associated with non-small cell lung cancer was analyzed by real-time quantitative polymerase chain reaction. RESULTS: An obvious apoptosis-promoting effect was found in A549 cells, which had been treated with 3% sevoflurane. The expression of several miRNAs that regulate apoptosis was significantly changed compared with the control group. CONCLUSION: Three percent sevoflurane can significantly increase the apoptosis rate of A549 cells, which may reduce the spread of cancer cells caused by operation. Sevoflurane disturbed the expression of the miRNAs that regulate apoptosis.