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

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

  • Eur J Pharmacol. 2026 Mar 28:1019:178674. doi: 10.1016/j.ejphar.2026.178674.
Lixia Tian 1,  Rongrong Yao 1,  Hui-Yuan Yi 1,  Yi-Xiao Guo 1,  Xue-Ru Liu 1,  Yu-Long Zhao 2,  Fu-Quan Huo 3,  Lingli Liang 4
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Institute of Neuroscience, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
  • 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Institute of Neuroscience, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China. Electronic address: [email protected].
  • 3 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Institute of Neuroscience, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China. Electronic address: [email protected].
  • 4 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Institute of Neuroscience, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China. Electronic address: [email protected].
PMID: 41740780 DOI: 10.1016/j.ejphar.2026.178674
Abstract

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.

Keywords

Basolateral amygdala; DNA methyltransferase 3A; Medial prefrontal cortex; Neuropathic pain; Paclitaxel; Ventrolateral periaqueductal gray.

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