Fluoxetine enhances the treatment of depression linked to opioid-induced constipation in mice by influencing the metabolomic profile

This study was intended to verify the potential role of Fluoxetine (Flx) in treating depression associated with opioid-induced constipation (OIC). We established a mouse model of chronic unpredictable mild stress (CUMS) and used loperamide to induce constipation based on the CUMS mice, generating a mouse model of depression associated with OIC (CUMS+OIC). The depressive behavior was evaluated via the open field and sucrose preference tests, while constipation was evaluated using defecation frequency and fecal water content. Liquid chromatography-mass spectrometry (LC-MS)-based metabolomics and bioinformatics analyses were performed. Treatment with Flx alleviated the depressive behavior of mice and inhibited OIC. We identified 153 differential metabolites between the control and the CUMS+OIC groups, among which 51 were downregulated while the other 102 were upregulated. These metabolites were involved in metabolic pathways such as pyrimidine metabolism, purine metabolism, and beta-alanine metabolism. Moreover, 64 differential metabolites between the Flx and the CUMS+OIC groups were involved in nicotinate and nicotinamide metabolism, and prion disease metabolism metabolic pathways. Through cluster analysis, we identified metabolites deregulated by CUMS+OIC and restored by Flx. Conclusively, Flx can improve the behavior and metabolic profile changes of CUMS associated with OIC, providing a basis for treating depression-related constipation.