S-ketamine alleviates morphine-induced hyperalgesia via decreasing the gut Enterobacteriaceae levels: Comparison with R-ketamine

Background: Opioid-induced hyperalgesia (OIH) is a serious complication during the pain treatment. Ketamine has been commonly reported to treat OIH, but the mechanisms remain unclear. Gut microbiota is recently recognized as one of the important mechanisms underlying the occurrence and treatment of OIH. However, whether ketamine enantiomers could alleviate OIH through gut microbiota that still needs to be clarified. Methods: The OIH model was established by morphine injection for 3 consecutive days, followed by hierarchical clustering analysis of behavioral results into susceptible or resilient group. Broad-spectrum antibiotic cocktail (ABx) was used to eradicated the gut microbiota of mice. Subsequently, fecal microbiota transplantation (FMT) was performed. S- or R-ketamine was administered as pretreatment 30 min before morphine injection. Fecal samples were collected for 16S rRNA gene sequencing after completion of all behavioral tests. Results: Approximately 60% of the mice developed OIH after morphine exposure with abnormal locomotion and anxiety-like behaviors. Pseudo germ-free mice treated with ABx did not develop hyperalgesia, whereas pseudo germ-free mice that received fecal microbiota transplantation from OIH mice developed hyperalgesia. Interestingly, S-ketamine but not R-ketamine rescued mice from OIH. The principal co-ordinates analysis (PCoA) suggested that the distribution of gut microbiota differed among the groups. Importantly, levels of Enterobacteriaceae were increased in OIH susceptible group, while decreased after S-ketamine treatment. Conclusion: S-ketamine but not R-ketamine was able to alleviate morphine-induced OIH, and this mechanism is probably related to decreasing the levels of gut Enterobacteriaceae.