METTL14-mediated m6A modification of TRPA1 promotes acute visceral pain induced by uterine cervical dilation by promoting NR2B phosphorylation

Guangfa Xia; Jing Qian; Yu Wang; Fei Xiao

doi:10.1016/j.cellsig.2025.111610

METTL14-mediated m6A modification of TRPA1 promotes acute visceral pain induced by uterine cervical dilation by promoting NR2B phosphorylation

Cell Signal. 2025 Jan 16:127:111610. doi: 10.1016/j.cellsig.2025.111610. Online ahead of print.

Authors

Guangfa Xia¹, Jing Qian², Yu Wang³, Fei Xiao⁴

Affiliations

¹ Department of Breast Surgery, Jiaxing University Affiliated Women and Children Hospital, Jiaxing 314050, Zhejiang Province, PR China.
² Department of Anesthesia, Jiaxing University Affiliated Women and Children Hospital, Jiaxing 314050, Zhejiang Province, PR China.
³ Department of Obstetrics and Gynecology, Jiaxing University Affiliated Women and Children Hospital, Jiaxing 314050, Zhejiang Province, PR China. Electronic address: [email protected].
⁴ Department of Anesthesia, Jiaxing University Affiliated Women and Children Hospital, Jiaxing 314050, Zhejiang Province, PR China. Electronic address: [email protected].

PMID: 39826676
DOI: 10.1016/j.cellsig.2025.111610

Abstract

Background: While TRPA1 serves as a therapeutic target for nociceptive pain, its role in acute visceral pain induced by uterine cervical dilation (UCD) remains an enigma. This study aims to elucidate the upstream and downstream mechanisms of TRPA1 in the context of UCD-induced acute visceral pain.

Methods: The UCD rats were administered with SAH (inhibitor of the METTL3-METTL14 complex) via intrathecal tubing. Validate UCD model by measuring spinal c-Fos expression and EMG. The levels of TRPA1 and p-NR2B were evaluated by qRT-PCR and western blot，and m6A level was detected by the kit. RNA Immunoprecipitation was adopted to determine the binding between TRPA1 and METTL14. Neurons were isolated from rat dorsal root ganglia (DRG), exposed to SAH treatment, and subsequently subjected to actinomycin D experiments.

Results: In the UCD model, cervical dilation causes an increase in EMG signal and spinal cord c-Fos expression. At the same time, the levels of TRPA1, p-NR2B, METTL14, and m6A increased in a stimulus intensity-dependent manner. Intrathecal SAH, a METTL3-METTL14 inhibitor, alleviated UCD-induced pain and reversed above indicators. Further investigation revealed that METTL14 binds to TRPA1, increasing TRPA1 mRNA stability via m6A modification.

Conclusion: METTL14 stabilizes TRPA1 through m6A modification, thereby promoting NR2B phosphorylation, culminating in acute visceral pain induced by UCD.

Keywords: Acute visceral pain; METTL14; TRPA1; m6A modification; p-NR2B.