A Dnmt3a-Mediated Epigenetic Mechanism for Chronic-Pain-Induced Behaviors of Negative Emotion in Mice

The comorbidity of chronic pain and associated negative emotion significantly worsens pain experience and pain chronicity, presenting a severe clinical problem. Despite extensive pre-clinical and clinical studies, the molecular mechanisms underlying the pain-negative-emotion comorbidity are still poorly understood. In this study, we explored an epigenetic mechanism for chronic-pain-induced negative emotion, focusing on the DNA methyltransferase 3a (Dnmt3a) in mice with chronic neuropathic pain. In the parabrachial nucleus (PBN), a brainstem gateway to transmitting pain signals from the peripheral to the brain, we found that chronic pain lasting one month induced anxiety- and depression-like behaviors and downregulated Dnmt3a protein. Overexpression of PBN Dnmt3a rescued the chronic pain mice from developing these behaviors of negative emotion, while knockdown of PBN Dnmt3a was sufficient to induce anxiety-like behavior in naive mice. In contrast, chronic pain increased expression of GluA1-pSer831 subunits of glutamate AMPA receptors in PBN. Dnmt3a knockdown increased both the expression of PBN GluA1-pSer831 and synaptic function of AMPA receptors in PBN neurons. Overexpression of PBN GluA1 induced anxiety-like behavior in naïve mice, whereas knockdown of PBN GluA1 produced an anxiolytic effect and prevented chronic-pain-induced anxiety-like behavior. These results suggest Dnmt3a as a key epigenetic modulator linking chronic pain to negative emotion behaviors through PBN, and PBN GluA1 as an important regulation target of Dnmt3a in the process.