Ferroptosis Regulated by 5-HT3a Receptor via Calcium/Calmodulin Signaling Contributes to Neuropathic Pain in Brachial Plexus Avulsion Rat Models

被引:0
作者
Liao, Chengpeng [1 ]
Guo, Jinding [2 ]
Li, Shenqian [2 ,3 ,4 ]
Rui, Jing [2 ,3 ,4 ,5 ]
Gao, Kaiming [3 ,5 ]
Lao, Jie [4 ,5 ]
Zhou, Yingjie [1 ,2 ,3 ]
机构
[1] Fudan Univ, Huashan Hosp, Dept Hand Surg, Shanghai 200040, Peoples R China
[2] NHC Key Lab Limbs Reconstruct, Shanghai 200032, Peoples R China
[3] Shanghai Key Lab Peripheral Nerve & Microsurg, Shanghai 200032, Peoples R China
[4] Inst Hand Surg, Shanghai 200040, Peoples R China
[5] Fudan Univ, Inst Hand Surg, Shanghai 200040, Peoples R China
来源
ACS CHEMICAL NEUROSCIENCE | 2024年 / 15卷 / 20期
基金
中国国家自然科学基金;
关键词
neuropathic pain; 5-HT3a receptor; ferroptosis; brachial plexus avulsion; L-type calciumchannel; INJURY; ACSL4;
D O I
10.1021/acschemneuro.4c00499
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Neuropathic pain is a prevalent complication following brachial plexus avulsion (BPA). Ferroptosis has been implicated in various nervous system disorders. However, the association between ferroptosis and neuropathic pain induced by BPA remains unclear. This study aimed to investigate the role of ferroptosis in BPA-induced neuropathic pain. A rat model of neuropathic pain was established via BPA induction. Pain thresholds of rats were measured after BPA surgery and intraperitoneal injection of Fer-1. On day 14 postsurgery, spinal dorsal horn (SDH) samples were collected for Western blotting, biochemical analysis, and immunohistochemistry to analyze the expression and distribution of ferroptosis-related markers. The relationships among 5-HT3a receptor, calcium/calmodulin (CaM) pathway, and ferroptosis were assessed via Western blotting, biochemical analysis, and lipid peroxidation assays, including iron and calcium content, reactive oxygen species, glutathione peroxidase 4 (GPX4), ACSL, and CaM expression. BPA-induced neuropathic pain was associated with iron accumulation, increased lipid peroxidation, dysregulated expression of Acyl-CoA synthetase long-chain family member 4, and GPX4, and changes in transferrin receptor, divalent metal transporter 1, and ferroportin-1 (FPN1). Intraperitoneal administration of Fer-1 reversed all of these alterations and mitigated mechanical and cold hypersensitivity. Inhibition of the 5-HT3a receptor reduced the extent of ferroptosis. Furthermore, the 5-HT3a receptor can regulate the calcium/CaM pathway via L-type calcium channels (LTCCs), and blocking LTCCs with nifedipine also alleviated ferroptosis in the SDH of BPA rats. Taken together, in rats with BPA, the development of neuropathic pain involves ferroptosis, which is regulated by the 5-HT3a receptor through the LTCCs and the calcium/CaM signaling pathway in the SDH.
引用
收藏
页码:3755 / 3766
页数:12
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