Long-lasting pain can induce depression, which seriously affects life quality of the patients, but little is known about the underlying mechanism. Chronic neuropathic pain can modulate DNA methylation in target genes related to neuroplasticity and mood regulation, which was induced by DNA methyltransferases (DNMTs). Methylation changes of brain-derived neurotrophic factor (Bdnf) in the hippocampus are critical for neuropathic pain and depression. Thus, we hypothesized that DNMTs are required for depression genesis, probably by repressing hippocampus Bdnf gene expression in rats with neuropathic pain, which can be rescued by ketamine. In the present study, rats were randomly subjected to spared nerve injury (SNI) or sham surgery. SNI upregulated DNMTs and downregulated Bdnf and exon I in the hippocampus and induced depression behaviors, whereas blocking the upregulation of DNMTs with RG108 alleviated SNI-induced depression by up-regulation of the expression of Bdnf and exon I. In addition, we showed that a single dose of ketamine could ameliorate SNI-induced depression-like behaviors, which was related to normalization of DNMTs and Bdnf. In conclusion, our study suggested that DNMTs-induced decreased expression of Bdnf may induce the comorbid of pain and depression, which can be prevented by ketamine.

持久的疼痛会诱发抑郁，严重影响患者的生活质量，但对其潜在机制知之甚少。慢性神经性疼痛可调节与基因可塑性和情绪调节有关的靶基因中的DNA甲基化，这是由DNA甲基转移酶（DNMT）诱导的。海马中脑源性神经营养因子（Bdnf）的甲基化变化对于神经性疼痛和抑郁至关重要。因此，我们假设抑郁症的发生可能需要DNMT，这可能是通过抑制神经性疼痛大鼠的海马Bdnf基因表达来实现的，氯胺酮可以挽救该疾病。在本研究中，大鼠随机接受了备用的神经损伤（SNI）或假手术。SNI上调DNMT并下调BDNF和外显子我在海马和诱发抑郁症的行为，而阻止与RG108转移酶的上调缓解SNI诱发抑郁症的表达上调BDNF和外显子一此外，我们发现，氯胺酮的单次剂量可能改善了SNI诱发的抑郁样行为，这与DNMT和Bdnf的正常化有关。总之，我们的研究表明，DNMTs诱导的Bd nf表达降低可能引起疼痛和抑郁并存，这可通过氯胺酮预防。