Sinomenine alleviates diabetic peripheral neuropathic pain through inhibition of the inositol‐requiring enzyme 1 alpha–X‐box binding protein 1 pathway by downregulating prostaglandin‐endoperoxide synthase 2

INTRODUCTION: We tried to show the effect of sinomenine (SIN) in diabetic peripheral neuropathic pain (DPNP) and the related underlying mechanism. METHODS: Network pharmacological analysis and bioinformatics analysis were carried out for identification of the active ingredients of Sinomenium acutum and the related genes. The DPNP rat model was constructed and primary rat spinal cord microglial cells were isolated for in vitro cell experiments. The therapeutic role of SIN in DPNP was determined in vivo and in vitro through analysis of microglial cell activation and inflammatory response. RESULTS: Therapeutic role of S. acutum in DPNP was mainly achieved by regulating 14 key genes, among which the target gene prostaglandin‐endoperoxide synthase 2 (PTGS2) of SIN might be the key gene. An in vivo experiment showed that SIN inactivated the inositol‐requiring enzyme 1 alpha–X‐box binding protein 1 pathway by downregulating PTGS2, which relieved pain symptoms in DPNP rats. It was confirmed in vivo that SIN inhibited the pathway through PTGS2 to alleviate the activation of spinal cord microglial cells and inflammatory response. CONCLUSION: SIN decreases the expression of PTGS2 to inactivate the inositol‐requiring enzyme 1 alpha–X‐box binding protein 1 signaling pathway, which inhibits microglial activation, as well as the release of inflammatory factors, thus alleviating DPNP.