Paper Title
FBXO3/HIPK2 MEDIATES CTBP1-DEPENDENT EPIGENETIC MECHANISMS IN THE DRG CONTRIBUTING TO THE DEVELOPMENT OF NEUROPATHIC PAIN

Abstract
Abstract - Neuropathic pain is a public health problem that has a debilitating effect on patients and decreases their quality of life. Emerging evidence supports the involvement of epigenetics in dorsal root ganglion (DRG) neurons relevant to neuropathic pain. We found that nerve injury increased C-terminal binding protein 1 (CtBP1), an important epigenetic transcriptional coregulators, to control µ-opioid receptor (MOR) transcriptional program in the DRG. Selective knockout of the gene encoding CtBP1 in DRG neurons completely blocked MOR gene silencing and neuropathic pain development after nerve injury. Remarkably, nerve injury leads to an increase in Foxp1, which recruits CtBP1 along with HDAC2 to reduce H3K9ac on the MOR promoter, consequently resulting in the downregulation of MOR within the dorsal root ganglion (DRG) during neuropathic pain. Additionally, nerve injury-induced Fbxo3, facilitating its-mediated HIPK2 ubiquitination while diminishing HIPK2-dependent CtBP1 ubiquitination, promoted the subsequent CtBP1-dependent epigenetic modification of MOR expression during nerve injury-induced neuropathic allodynia.Intrathecal administration of CtBP1 siRNA, NSC 95397 (a CtBP1 inhibitor), Foxp1 siRNA, HIPK2 siRNA, or BC-1215 (Fbxo3 inhibitor) into nerve-injured rats alleviated allodynia, providing confirmation of the hierarchical and interactive nature of this cascade within the DRG during neuropathic pain. In summary, our findings indicate that Fbxo3/HIPK2 in the DRG contributes to nerve injury-induced neuropathic pain development by regulating CtBP-dependent epigenetic mechanisms. Keywords - CtBP1, MOR, HIPK, Foxp1,HDAC2, Neuropathic Allodynia.