组胺 H4 受体和 TRPV1 介导微生物组代谢物尸胺诱发的瘙痒。

IF 2.8 3区 医学 Q2 NEUROSCIENCES
Shi-Yu Sun, Xi Yin, Jun-Yi Ma, Xue-Long Wang, Xue-Mei Xu, Jing-Ni Wu, Cheng-Wei Zhang, Ying Lu, Tong Liu, Li Zhang, Pei-Pei Kang, Bin Wu, Guo-Kun Zhou
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引用次数: 0

摘要

尸胺是肠道微生物组产生的一种内源性代谢物,在生理和病理条件下具有多种活性。然而,尸胺是否能调节疼痛或瘙痒仍不清楚。在这项研究中,我们首先通过分子对接模拟发现,尸胺可与组胺4受体(H4R)结合,且对接能得分更高,这表明尸胺可能是H4R的内源性配体。我们随后发现,在小鼠颈部或脸颊皮内注射尸胺可诱发剂量依赖性的小鼠搔抓反应,而选择性 H4R 拮抗剂 JNJ-7777120、瞬时受体电位类香草素 1(TRPV1)拮抗剂卡扎西平和 PLC 抑制剂 U73122 可抑制这种反应,但 H1R 拮抗剂、TRPA1 拮抗剂或 TRPV4 拮抗剂不能抑制这种反应。同样,Trpv1-/-小鼠而非 Trpa1-/- 小鼠的尸体诱发的瘙痒也会消失。scRNA-Seq 数据分析显示,H4R 和 TRPV1 主要在 NP2、NP3 和 PEP1 DRG 神经元上共表达。钙成像分析表明,尸胺灌注增强了离体背根神经节(DRG)神经元的钙离子流入,JNJ-777120和卡扎西平抑制了钙离子流入,Trpv1-/-小鼠的DRG神经元也是如此。膜片钳记录发现,尸胺灌注能显著提高小直径 DRG 神经元的兴奋性,而 JNJ-7777120 能消除这种效应,这表明 H4R 参与其中。综上所述,这些结果证明了尸胺是一种新型的内源性瘙痒诱导剂,可激活初级感觉神经元中的H4R/TRPV1信号通路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Histamine H4 receptor and TRPV1 mediate itch induced by cadaverine, a metabolite of the microbiome.

Cadaverine is an endogenous metabolite produced by the gut microbiome with various activity in physiological and pathological conditions. However, whether cadaverine regulates pain or itch remains unclear. In this study, we first found that cadaverine may bind to histamine 4 receptor (H4R) with higher docking energy score using molecular docking simulations, suggesting cadaverine may act as an endogenous ligand for H4R. We subsequently found intradermal injection of cadaverine into the nape or cheek of mice induces a dose-dependent scratching response in mice, which was suppressed by a selective H4R antagonist JNJ-7777120, transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine and PLC inhibitor U73122, but not H1R antagonist or TRPA1 antagonist or TRPV4 antagonist. Consistently, cadaverine-induced itch was abolished in Trpv1-/- but not Trpa1-/- mice. Pharmacological analysis indicated that mast cells and opioid receptors were also involved in cadaverine-induced itch in mice. scRNA-Seq data analysis showed that H4R and TRPV1 are mainly co-expressed on NP2, NP3 and PEP1 DRG neurons. Calcium imaging analysis showed that cadaverine perfusion enhanced calcium influx in the dissociated dorsal root ganglion (DRG) neurons, which was suppressed by JNJ-7777120 and capsazepine, as well as in the DRG neurons from Trpv1-/- mice. Patch-clamp recordings found that cadaverine perfusion significantly increased the excitability of small diameter DRG neurons, and JNJ-7777120 abolished this effect, indicating involvement of H4R. Together, these results provide evidences that cadaverine is a novel endogenous pruritogens, which activates H4R/TRPV1 signaling pathways in the primary sensory neurons.

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来源期刊
Molecular Pain
Molecular Pain 医学-神经科学
CiteScore
5.60
自引率
3.00%
发文量
56
审稿时长
6-12 weeks
期刊介绍: Molecular Pain is a peer-reviewed, open access journal that considers manuscripts in pain research at the cellular, subcellular and molecular levels. Molecular Pain provides a forum for molecular pain scientists to communicate their research findings in a targeted manner to others in this important and growing field.
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