Institute of Neuroscience, National Yang Ming Chiao Tung University, Yang Ming Campus, Taipei 112, Taiwan.
Institute of Neuroscience, National Yang Ming Chiao Tung University, Yang Ming Campus, Taipei 112, Taiwan.
Neurosci Lett. 2022 Nov 1;790:136890. doi: 10.1016/j.neulet.2022.136890. Epub 2022 Sep 28.
Neuropathic pain is a serious health problem, but optimal drug treatments remain lacking. It has been known that the compound NS5806 is a Kv4.3 activator, which increases Kv4.3-mediated K current to reduce neuronal excitability. In this study, we investigated the molecular and cellular mechanisms underlying the analgesic effect of NS5806 in neuropathic pain induced by peripheral nerve injury. Using lumbar (L)5/L6 spinal nerve ligation (SNL) in rats, we found that, without changing the basal nociception, the analgesic effect of NS5806 (220 μg/kg) peaked at 4 h and lasted for 8 h after intraperitoneal injection. Multiple doses of NS5806 reduced not only SNL-upregulated proinflammatory mediators in the DRG and spinal cord on day 1 and day 4 after L5/L6 SNL, but also SNL-evoked expansion of DRG macrophages and spinal microglia on day 4. Furthermore, at 10 min after L5 SNL, NS5806 pretreatment for 4 h suppressed SNL-induced phosphorylated extracellular signal-regulated kinase (pERK) in both Kv4.3 and Kv4.3 neurons in the dorsal root ganglion (DRG) and superficial spinal dorsal horn, indicating that the action of NS5806 is not restricted to Kv4.3 neurons. In vitro kinase activity assays revealed that NS5806 weakly inhibited ERK2, MEK1, MEK2, and c-Raf in the ERK pathway. Since NS5806 and the ERK pathway inhibitors have similar antinociceptive characteristics, this study suggests that NS5806 also acts as an ERK pathway inhibitor to attenuate neuropathic pain.
神经性疼痛是一种严重的健康问题，但仍缺乏最佳的药物治疗方法。已知化合物 NS5806 是一种 Kv4.3 激活剂，可增加 Kv4.3 介导的 K 电流以降低神经元兴奋性。在这项研究中，我们研究了 NS5806 在周围神经损伤引起的神经性疼痛中的镇痛作用的分子和细胞机制。我们使用大鼠腰椎（L）5/L6 脊神经结扎（SNL）发现，在不改变基础痛觉的情况下，NS5806（220μg/kg）的镇痛作用在腹腔注射后 4 小时达到峰值，并持续 8 小时。多次给予 NS5806 不仅减少了 L5/L6 SNL 后第 1 天和第 4 天 DRG 和脊髓中上调的促炎介质，而且还减少了 L5/L6 SNL 后第 4 天 DRG 巨噬细胞和脊髓小胶质细胞的扩张。此外，在 L5 结扎后 10 分钟，NS5806 预处理 4 小时可抑制 SNL 诱导的背根神经节（DRG）和浅层脊髓背角中 Kv4.3 和 Kv4.3 神经元中的磷酸化细胞外信号调节激酶（pERK），表明 NS5806 的作用不仅限于 Kv4.3 神经元。体外激酶活性测定显示，NS5806 可弱抑制 ERK 通路中的 ERK2、MEK1、MEK2 和 c-Raf。由于 NS5806 和 ERK 通路抑制剂具有相似的镇痛特性，因此本研究表明 NS5806 还作为 ERK 通路抑制剂来减轻神经性疼痛。
