Osteoarthritis (OA) is a highly prevalent and disabling joint disease, characterized by pathological progressive joint deformation and clinical symptoms of pain. Disease-modifying treatments remain unavailable, and pain-mitigation is often suboptimal, but recent studies suggest beneficial effects by inhibition of the voltage-gated sodium channel NaV1.7. We previously identified compound 194 as an indirect inhibitor of NaV1.7 by preventing SUMOylation of the NaV1.7-trafficking protein, collapsin response mediator protein 2. Compound 194 reduces the functional activity of NaV1.7 channels and produces effective analgesia in a variety of acute and neuropathic pain models. However, its effectiveness has not yet been evaluated in models of OA. Here, we explore the effects of 194 on pain-related outcomes in the OA-like monoiodoacetate model using behavioral assessment, biochemistry, novel in vivo fiber photometry, and patch clamp electrophysiology. We found that the monoiodoacetate model induced (1) increased pain-like behaviors and calcium responses of glutamatergic neurons in the parabrachial nucleus after evoked cold and mechanical stimuli, (2) conditioned place aversion to mechanical stimulation, (3) functional weight bearing asymmetry, (4) increased sodium currents in dorsal root ganglia neurons, and (5) increased calcitonin gene-related peptide-release in the spinal cord. Crucially, administration of 194 improved all these pain-related outcomes. Collectively, these findings support indirect inhibition of NaV1.7 as an effective treatment of OA-related pain through the inhibition of collapsin response mediator protein 2-SUMOylation via compound 194.

中文翻译：

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通过抑制 CRMP2-Ubc9 相互作用靶向 NaV1.7 的小分子可降低啮齿动物骨关节炎模型中与疼痛相关的结局。


骨关节炎 （OA） 是一种非常普遍的致残性关节疾病，其特征是病理性进行性关节变形和疼痛的临床症状。疾病缓解治疗仍然不可用，疼痛缓解通常不是最佳的，但最近的研究表明，抑制电压门控钠通道 NaV1.7 会产生有益效果。我们之前通过阻止 NaV1.7 运输蛋白、塌陷蛋白反应介质蛋白 2 的 SUMO化，将化合物 194 确定为 NaV1.7 的间接抑制剂。化合物 194 降低 NaV1.7 通道的功能活性，并在各种急性和神经性疼痛模型中产生有效的镇痛作用。然而，其有效性尚未在 OA 模型中进行评估。在这里，我们使用行为评估、生物化学、新型体内纤维光度测定和膜片钳电生理学探讨了 194 对 OA 样单碘乙酸模型中疼痛相关结果的影响。我们发现单碘乙酸模型诱导 （1） 在诱发寒冷和机械刺激后，臂旁核谷氨酸能神经元的疼痛样行为和钙反应增加，（2） 对机械刺激的条件性地方厌恶，（3） 功能性负重不对称，（4） 背根神经节神经元中的钠电流增加，以及 （5） 脊髓中降钙素基因相关肽释放的增加。至关重要的是，194 的给药改善了所有这些与疼痛相关的结局。总的来说，这些发现支持间接抑制 NaV1.7 作为通过化合物 194 抑制塌陷反应介导蛋白 2-SUMOylation 的有效治疗 OA 相关疼痛。