通过药理作用使 NaV1.8 通道降解,从而减轻神经性疼痛。

IF 5.9 1区 医学 Q1 ANESTHESIOLOGY
PAIN® Pub Date : 2025-05-01 Epub Date: 2024-11-08 DOI:10.1097/j.pain.0000000000003470
Molly K Martin, Raider Rodriguez, Giselle Guerrero, Garrett D Sheehan, Rasheen Powell, Amanda H Klein, Arin Bhattacharjee
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引用次数: 0

摘要

摘要:在二期临床试验中,NaV1.8 通道被确定为治疗急性疼痛的可行靶点。然而,结果并不理想,NaV1.8 通道阻滞剂必须全身使用,可能会导致不良反应,尤其是在长期使用期间。一种局部、持久的方法是可取的,但局部麻醉剂既无特异性也不持久。我们展示了一种针对 NaV1.8 通道支架和降解的药理学方法,这种方法可减轻小鼠的神经病理性疼痛行为,从而取代孔阻滞剂方法。NaV1.8 通道与名为 Magi-1 的含 WW 结构域的支架蛋白相互作用。WW 结构域通常存在于泛素连接酶中,而 NaV1.8 通道很容易被泛素连接酶降解。在这里,我们展示了 NaV1.8 和 MAGI-1 在人体组织中的共定位。我们证明,源自 NaV1.8 WW 结合域的脂质化多肽在亚微摩浓度下可抑制啮齿动物背根神经节神经元的发射。该肽能降低人背根神经节神经元中 NaV1.8 通道的免疫活性和河豚毒素抗性电流。我们发现,脂质化多肽在小鼠体内注射一次后,可持续数周减轻神经病理性疼痛行为。我们的研究结果表明,NaV1.8 靶向脂化肽可提供局部和持续的镇痛效果,是 NaV1.8 孔阻滞剂的可行替代品。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pharmacologically enabling the degradation of Na V 1.8 channels to reduce neuropathic pain.

Abstract: In phase II clinical trials, Na V 1.8 channels were identified as viable targets to treat acute pain. Results were modest, however, and Na V 1.8 pore blockers must be given systemically, potentially leading to adverse effects, especially during prolonged use. A local, long-lasting approach is desirable, yet local anesthetics are neither specific nor long-lasting. In lieu of a pore blocker approach, we show a pharmacological method targeting the scaffolding and degradation of Na V 1.8 channels, which attenuated neuropathic pain behavior in mice. Na V 1.8 channels interact with the WW domain-containing scaffold protein called Magi-1. WW domains are typically found in ubiquitin ligases, and Na V 1.8 channels are susceptible to degradation by ubiquitin ligases. Here, we show Na V 1.8 and MAGI-1 colocalized in human tissues. We demonstrate that a lipidated peptide derived from the Na V 1.8 WW binding domain, at sub-micromolar concentrations, inhibited rodent dorsal root ganglion neuronal firing. The peptide reduced Na V 1.8 channel immunoreactivity and tetrodotoxin-resistant currents in human dorsal root ganglion neurons. We found that the lipidated peptide attenuated neuropathic pain behaviors in mice for multiple weeks after a single injection. Our results reveal that the Na V 1.8-targeted lipidated peptide provides local and sustained analgesia, serving as a viable alternative to Na V 1.8 pore blockers.

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来源期刊
PAIN®
PAIN® 医学-临床神经学
CiteScore
12.50
自引率
8.10%
发文量
242
审稿时长
9 months
期刊介绍: PAIN® is the official publication of the International Association for the Study of Pain and publishes original research on the nature,mechanisms and treatment of pain.PAIN® provides a forum for the dissemination of research in the basic and clinical sciences of multidisciplinary interest.
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