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S-ketamine alleviates morphine-induced hyperalgesia via decreasing the gut Enterobacteriaceae levels: Comparison with
Hanyu Liu1, Siqi Yang2, Qi Zhang2
1Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Department of Anesthesiology, Perioperative and Pain Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 210029, China.
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.
Insights
S-ketamine, but not R-ketamine, effectively treats opioid-induced hyperalgesia (OIH) by modulating gut microbiota, specifically reducing Enterobacteriaceae levels. This research clarifies a key mechanism in OIH treatment.
Area of Science:
- Neuroscience
- Microbiology
- Pharmacology
Background:
- Opioid-induced hyperalgesia (OIH) is a significant clinical challenge in pain management.
- Ketamine is recognized for OIH treatment, yet its precise mechanisms, particularly concerning gut microbiota, remain elusive.
- The gut microbiota's role in OIH development and treatment is an emerging area of investigation.
Purpose of the Study:
- To investigate whether ketamine enantiomers (S-ketamine and R-ketamine) alleviate OIH through modulation of the gut microbiota.
- To elucidate the specific changes in gut microbial composition associated with OIH and its treatment with ketamine enantiomers.
Main Methods:
- An opioid-induced hyperalgesia (OIH) mouse model was established using chronic morphine administration.
- Gut microbiota was depleted using broad-spectrum antibiotics (ABx), followed by fecal microbiota transplantation (FMT) from OIH-susceptible donors.
- Mice were pretreated with S- or R-ketamine before morphine exposure; fecal samples were analyzed using 16S rRNA gene sequencing.
Main Results:
- Approximately 60% of mice developed OIH, exhibiting abnormal behaviors.
- Antibiotic treatment prevented OIH, while FMT from OIH mice induced hyperalgesia, confirming the microbiota's role.
- S-ketamine, but not R-ketamine, ameliorated OIH and significantly altered gut microbial composition, notably decreasing Enterobacteriaceae levels.
Conclusions:
- S-ketamine demonstrates efficacy in alleviating morphine-induced OIH, whereas R-ketamine does not.
- The therapeutic effect of S-ketamine on OIH is likely mediated by its ability to reduce the abundance of gut Enterobacteriaceae.
- This study highlights the gut microbiota as a critical target for managing OIH.
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