Exploring the synergistic mechanism of combined hypnotic drugs on sleep in mice based on transcriptomics

To investigate the effects of the combined administration of dexmedetomidine and eszopiclone on sleep in mice, and to elucidate the underlying molecular mechanisms at the gene expression level.

Taking the loss of righting reflex in mice as sleep indicator, the drug interactions between dexmedetomidine and eszopiclone were systematically evaluated at nine ratios by the Chou-Talalay method. Transcriptome sequencing was applied to screen for key pathways and genes through differentially expressed genes analysis, GO functional annotation and KEGG enrichment analysis. Additionally, qRT-PCR was used to validate the screened key genes.

dexmedetomidine and eszopiclone exhibited synergistic hypnotic effects at ED₅₀ ratios of 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2 and 9:1, with the strongest synergism occurring at the equal ratio (5:5). The combination group showed significant enrichment in the neuroactive ligand-receptor interaction pathway. Within this pathway, expression of the genes Gh and Prl was significantly upregulated, whereas that of Glra1, Npsr1 and Trpv1 was significantly downregulated. These expression changes were confirmed by qRT-PCR.

The study reveals that co-administration of dexmedetomidine and eszopiclone produces a significant synergistic hypnotic effect in mice, with the strongest synergy demonstrated when the drugs are combined at the equal ratio. The underlying mechanism mediating their synergistic modulation of sleep may be associated with the upregulation of Gh and Prl genes as well as the downregulation of Glra1, Npsr1 and Trpv1 genes in the neuroactive ligand-receptor interaction pathway.