In phase II clinical trials, NaV1.8 channels were identified as viable targets to treat acute pain. Results were modest, however, and NaV1.8 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 NaV1.8 channels, which attenuated neuropathic pain behavior in mice. NaV1.8 channels interact with the WW domain-containing scaffold protein called Magi-1. WW domains are typically found in ubiquitin ligases, and NaV1.8 channels are susceptible to degradation by ubiquitin ligases. Here, we show NaV1.8 and MAGI-1 colocalized in human tissues. We demonstrate that a lipidated peptide derived from the NaV1.8 WW binding domain, at sub-micromolar concentrations, inhibited rodent dorsal root ganglion neuronal firing. The peptide reduced NaV1.8 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 NaV1.8-targeted lipidated peptide provides local and sustained analgesia, serving as a viable alternative to NaV1.8 pore blockers.

中文翻译：

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药理学上使 NaV1.8 通道降解以减轻神经性疼痛。


在 II 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，结果不大，必须全身给予 NaV1.8 毛孔阻滞剂，这可能会导致不良反应，尤其是在长期使用期间。局部、持久的方法是可取的，但局部麻醉既不具体也不持久。代替孔阻滞剂方法，我们展示了一种针对 NaV1.8 通道的支架和降解的药理学方法，该方法减轻了小鼠的神经性疼痛行为。NaV1.8 通道与包含 WW 结构域的支架蛋白（称为 Magi-1）相互作用。WW 结构域通常存在于泛素连接酶中，而 NaV1.8 通道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，亚微摩尔浓度下源自 NaV1.8 WW 结合域的脂质化肽抑制啮齿动物背根神经节神经元放电。该肽降低了人背根神经节神经元中的 NaV1.8 通道免疫反应性和河豚毒素抗性电流。我们发现脂质化肽在单次注射后数周内减轻了小鼠的神经性疼痛行为。我们的结果表明，NaV1.8 靶向脂质肽提供局部和持续的镇痛，是 NaV1.8 孔阻滞剂的可行替代品。