Dexmedetomidine Alleviates Visceral Pain by Modulating a Pro-Inflammatory Macrophage-Associated Gene Network

Background/Objectives: The clinical management of visceral pain remains a significant challenge. Our previous study confirmed the analgesic efficacy of dexmedetomidine (Dex) in a mouse model of inflammatory visceral pain (IVP). However, the underlying molecular mechanism, particularly regarding immune regulation, has not been fully elucidated. Methods: In the present study, transcriptomic profiling of both physiological and disease states was performed to characterize associated molecular and immune signatures. Key driver genes were identified by integrating differentially expressed genes (DEGs) from the IVP model with potential Dex targets derived from network pharmacology. Molecular docking simulations evaluated binding interactions. The correlations between Dex's targets and immune cell infiltration patterns, with a focus on macrophages, were analyzed. Results: Multi-tissue analysis revealed a strong association between IVP pathogenesis and pro-inflammatory immune responses, specifically a shift in macrophage polarization. Within this dysregulated network, seven proteins were identified as direct potential targets of Dex. Among these, six core targets, such as ADGRF1, IDO1, JAK3 and NR1H4, demonstrated the most significant correlations with M1-like macrophages and exhibited strong in silico binding potential with Dex. Conclusions: This integrated analysis suggests that Dex may alleviate visceral pain by modulating a specific gene network linked to pro-inflammatory macrophage activation, thereby promoting the restoration of immune balance. Our findings provide a novel mechanism-informed perspective for the application of Dex in visceral pain therapy.