氯胺酮及代谢物对慢性疼痛所致抑郁的改善作用与肠道菌群关系的研究

氯胺酮及其代谢物具有抗抑郁作用。我们前期工作证实该点，并指出氯胺酮的抗抑郁作用与改善肠道菌群紊乱有关。慢性疼痛是抑郁发病的重要诱因，我们最新研究观察到氯胺酮对慢性神经病理性疼痛（CNP）所致抑郁易感型具有治疗作用，且在CNP动物模型中抑郁易感型肠道菌群组成与抑郁非易感型显著不同。这些结果提示：氯胺酮及其代谢物对慢性疼痛所致抑郁易感型具有治疗作用，且其机制可能与改善肠道菌群紊乱有关。本课题拟通过慢性疼痛抑郁易感模型观察氯胺酮及其代谢物【R-和S-去甲氯胺酮、(2R,6R)-和(2S,6S)-羟基去甲氯胺酮】对其治疗作用，并通过16S rRNA测序及宏基因组学探讨肠道菌群的作用及可能机制。再者，我们拟研究迷走神经功能调节下的肠道菌群改变在慢性疼痛所致抑郁发病及氯胺酮治疗作用中的可能机制。该研究可为开发氯胺酮及其代谢物治疗疼痛抑郁共病提供理论依据，并可拓宽肠道菌群的研究领域。

Ketamine and its metabolites have antidepressant effects. Our previous studies confirmed this point and demonstrated that the antidepressant effects of ketamine are related to the improvement of the abnormality in the composition of gut microbiota. Chronic pain is an important cause for depression. Very recently, we reported that ketamine has antidepressant effects in chronic neuropathic pain (CNP)-inudced depression susceptible rats, and that the composition of gut microbiota in depression susceptible rats induced by CNP is different from the unsusceptible phenotype. Based on these findings, we propose a scientific hypothesis that ketamine and its metabolites have beneficial effects to improve depressive symptoms in chronic pain-induced model, and its therapeutic mechanisms are probably associated with the restoration of the abnormality in gut microbiota composition. We therefore apply chronic pain-induced depression models to investigate the antidepressant effects of ketamine and its metabolites [(R)- and (S)-norketamine, (2R,6R)-hydroxynorketamine and (2S,6S)- hydroxynorketamine], and to determine the role of gut microbiota by 16S rRNA sequencing and metagenomics. Furthermore, we aim to study the role of vagus nerve-mediated changes of gut microbiota in the pathogenesis of pain-induced depression and possible therapeutic mechanisms of ketamine and its metabolites. Our findings could provide a theoretical basis for the development of ketamine and its metabolites for the treatment of pain and depression, and broaden the research field of gut microbiota.