调节G蛋白激活,电流和阿片类受体酸化由pH依赖的抗受体激动剂NFEPP
Melih Özgür Celik1, Viola Seitz1, Fatih Yergöz1
1Department of Experimental Anesthesiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Frontiers in molecular neuroscience
|May 30, 2023
概括
通过向酸性组织中的mu-opioid受体 (MOR),N-(3-fluoro-1-phenethylpiperidine-4-yl) -N-phenyl propionamide (NFEPP) 有效地减少疼痛. 这种新型的止痛药可以缓解疼痛.
科学领域:
- 神经科学是一个神经科学.
- 药理学 药理学是指药理学的学科.
- 疼痛研究 疼痛研究
背景情况:
- N-(3-fluoro-1-phenethylpiperidine-4-yl) -N-phenyl propionamide (NFEPP) 是一种新型止痛药,向酸性受伤组织中的片受体 (MOR).
- 在酸性环境中NFEPP的选择性行动旨在避免与正常pH作用的常规阿片类药物相关的中心副作用.
- 精确的神经元机制的NFEPP的抗感受作用,特别是其与电压依赖通道 (VDCCs) 在感受神经元的相互作用,需要详细调查.
研究的目的:
- 为了研究NFEPP对大鼠背根质神经元 (DRG) 的电流的影响,在酸性和正常pH.
- 阐明G蛋白子单元 (Gαi和Gβγ) 在介导NFEPP抑制VDCCs中的作用.
- 为了比较NFEPP与常规阿片类药物agonist fentanyl的pH依赖活性.
主要方法:
- 在大鼠DRG神经元中的电流的电生理记录.
- 使用百日咳毒素和蛋白来分别抑制Gαi和Gβγ亚单元.
- 评估GTPγS结合,信号传递和MOR酸化对NFEPP和芬太尼在不同pH水平的反应.
主要成果:
- 与正常pH相比,NFEPP在低pH下在HEK293细胞中显示出更有效的G蛋白激活.
- 在低pH下,NFEPP显著抑制了去极化DRG神经元中的VDCCs,这种效应由Gβγ子单元介导.
- 由NFEPP诱导的MOR酸化依赖于pH值,而芬太尼的作用不受pH值变化的影响.
结论:
- 在酸性条件下,NFEPP介导的片受体信号增强.
- NFEPP的抗受体作用归因于DRG神经元中通道的抑制,特别是在酸性pH下.
- 由于其pH选择性机制,NFEPP代表了治疗疼痛的有前途的治疗策略,具有潜在的改善副作用概况.
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