Repeated (S)-ketamine administration ameliorates the spatial working memory impairment in mice with chronic pain: role of the gut microbiota–brain axis

ABSTRACT

Chronic pain is commonly linked with diminished working memory. This study explores the impact of the anesthetic (S)-ketamine on spatial working memory in a chronic constriction injury (CCI) mouse model, focusing on gut microbiome. We found that multiple doses of (S)-ketamine, unlike a single dose, counteracted the reduced spontaneous alteration percentage (%SA) in the Y-maze spatial working memory test, without affecting mechanical or thermal pain sensitivity. Additionally, repeated (S)-ketamine treatments improved the abnormal composition of the gut microbiome (β-diversity), as indicated by fecal 16S rRNA analysis, and increased levels of butyrate, a key gut – brain axis mediator. Protein analysis showed that these treatments also corrected the upregulated histone deacetylase 2 (HDAC2) and downregulated brain-derived neurotrophic factor (BDNF) in the hippocampi of CCI mice. Remarkably, fecal microbiota transplantation from mice treated repeatedly with (S)-ketamine to CCI mice restored %SA and hippocampal BDNF levels in CCI mice. Butyrate supplementation alone also improved %SA, BDNF, and HDAC2 levels in CCI mice. Furthermore, the TrkB receptor antagonist ANA-12 negated the beneficial effects of repeated (S)-ketamine on spatial working memory impairment in CCI mice. These results indicate that repeated (S)-ketamine administration ameliorates spatial working memory impairment in CCI mice, mediated by a gut microbiota – brain axis, primarily through the enhancement of hippocampal BDNF – TrkB signaling by butyrate.

KEYWORDS:

• Chronic pain
• spatial working memory
• hippocampus
• gut–brain axis
• gut microbiota
• (s)-ketamine

Acknowledgments

The authors would like to thank the staff of the Chen Guiquan Laboratory of the Model Animal Research Center of Nanjing University (MARC).

Disclosure statement

Dr. Hashimoto is the inventor of filed patent applications on “The use of R-Ketamine in the treatment of psychiatric diseases,” “(S)-norketamine and salt thereof as pharmaceutical,” “R-Ketamine and derivative thereof as prophylactic or therapeutic agent for neurodegeneration disease or recognition function disorder,” “Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases,” “R-Ketamine and its derivatives as a preventive or therapeutic agent for a neurodevelopmental disorder,” and “Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases” by the Chiba University. Dr. K. Hashimoto has also received speaker honoraria, consultant fees, and research support from Abbott, Boehringer Ingelheim, Daiichi-Sankyo, Meiji Seika Pharma, Seikagaku Corporation, Sumitomo-Pharma, Taisho, Otsuka, Murakami Farm, and Perception Neuroscience. The other authors have no conflicts of interest to declare.

Authors’ contributions

MW, KH, JY, and ZZ designed this study. YJ, JC, and YZ performed experiments. YJ analyzed the data. YJ, MW, JY, and ZZ drafted a significant portion of this manuscript. KH directed the discussion and revised the manuscript accordingly. All authors have read and approved the final manuscript.

Availability of data and materials

The data obtained in the current study are available from the corresponding authors upon reasonable request.

Data and code availability

The 16s rRNA sequencing data were deposited in the NCBI Sequence Read Archive and are available under the accession number PRJNA951678.

Ethics approval

The protocol of this study was approved by the Animal Care and Use Committee of Southern Medical University.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2310603

Additional information

Funding

This study was supported by grants from the National Natural Science Foundation of China (to Jian-Jun Yang, 82171189 and to Xingming Wang, 81901139). This study was also supported by the Program of Introducing Talents of Discipline to Universities of Henan. Project name: Anesthesia and Brain Research. Project No. CXJD2019008 (to Jian-Jun Yang).