DNMT3A-regulated medial prefrontal cortex circuits modulate paclitaxel-induced neuropathic pain.

The medial prefrontal cortex (mPFC) and its connections with regions such as the periaqueductal gray (PAG) and basolateral amygdala (BLA) have been functionally implicated in pain processing. However, how these neural circuits adaptively reorganize under chronic pain conditions remains poorly understood. We recently demonstrated that paclitaxel (PTX) induces hypomethylation in the mPFC as a consequence of DNA methyltransferase 3 A (DNMT3A) downregulation, thereby promoting PTX-induced neuropathic pain in mice. The present study aims to investigate the role of DNMT3A-regulated neural circuits in this process. Using an adeno-associated virus-based transsynaptic tracing strategy, we demonstrate that overexpression of DNMT3A in the mPFC-ventrolateral PAG (vlPAG) circuit alleviates PTX-induced pain hypersensitivity. Similarly, DNMT3A overexpression in the mPFC-BLA circuit reduces thermal hyperalgesia. Furthermore, we examined the effect of DNMT3A overexpression on gene expression profiles in the mPFC under PTX-induced pain conditions and identified 1131 differentially expressed genes associated with the mPFC-vlPAG circuit. Together, these findings elucidate the specific role of mPFC DNMT3A in modulating pain via the mPFC-vlPAG and mPFC-BLA circuits in a model of PTX-induced neuropathic pain.