AUTHOR=Li Guangling , Wang Chao 

TITLE=NGF/ERK signaling-mediated epigenetic regulation of neuropathic pain in the cerebrospinal fluid-contacting nucleus

JOURNAL=Frontiers in Neurology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1641450

DOI=10.3389/fneur.2025.1641450

ISSN=1664-2295

ABSTRACT=ObjectiveNeuropathic pain (NP) is a debilitating condition that is associated with multiple molecular alterations in the nervous system. This is the first study to demonstrate the epigenetic regulatory function of nerve growth factor (NGF), mediated through the extracellular signal-regulated kinase (ERK) signaling pathway in the cerebrospinal fluid-contacting nucleus (CSF-CN), in relation to NP. The objective of this study was to characterize the role of NGF in this specific brain region and its downstream effects on histone acetylation in the chronic constriction injury (CCI) rat model.MethodsA rat model of NP was established using CCI. The study investigated the expression of NGF and its impact on pain pathways. NGF levels in the CSF-CN were assessed, and the effects of NGF on neuropathic pain were evaluated by administering NGF antibodies and ERK antagonists. Immunohistochemistry and Western blotting were used to measure key molecular markers, including p-ERK, THMA, and acetylated histone H3K56. Statistical analysis was performed, with significance set at a p-value of < 0.05.ResultsCI induced significant upregulation of NGF in the CSF-CN. Treatment with NGF antibodies alleviated NP symptoms and reduced p-ERK levels in the CSF-CN. ERK antagonists further diminished thermal hyperalgesia and mechanical allodynia (THMA) and decreased the expression of acetylated histone H3K56.ConclusionThis is the first study to identify an NGF/ERK/ acetylated histone H3 (Ac-H3) signaling axis in the CSF-CN as a central mediator of neuropathic pain through epigenetic modulation. Our results suggest that targeting this novel signaling pathway may provide new therapeutic strategies for managing NP.