TAFA4 通过 LDL 受体和调制脊髓 A 型钾电流缓解损伤诱导的机械性超敏反应。

TAFA4 relieves injury-induced mechanical hypersensitivity through LDL receptors and modulation of spinal A-type K current.

机构信息

Aix-Marseille Université, CNRS, Institut de Biologie du Développement de Marseille, UMR 7288, Case 907, 13288 Marseille Cedex 09, France.

Phenotype Expertise, 5 Boulevard du Maréchal Koenig, 13009 Marseille, France.

出版信息

Cell Rep. 2021 Oct 26;37(4):109884. doi: 10.1016/j.celrep.2021.109884.

DOI:10.1016/j.celrep.2021.109884

PMID:34706225

Abstract

Pain, whether acute or persistent, is a serious medical problem worldwide. However, its management remains unsatisfactory, and new analgesic molecules are required. We show here that TAFA4 reverses inflammatory, postoperative, and spared nerve injury (SNI)-induced mechanical hypersensitivity in male and female mice. TAFA4 requires functional low-density lipoprotein receptor-related proteins (LRPs) because their inhibition by RAP (receptor-associated protein) dose-dependently abolishes its antihypersensitive actions. SNI selectively decreases A-type K current (I) in spinal lamina II outer excitatory interneurons (L-IIo ExINs) and induces a concomitant increase in I and decrease in hyperpolarization-activated current (I) in lamina II inner inhibitory interneurons (L-IIi InhINs). Remarkably, SNI-induced ion current alterations in both IN subtypes were rescued by TAFA4 in an LRP-dependent manner. We provide insights into the mechanism by which TAFA4 reverses injury-induced mechanical hypersensitivity by restoring normal spinal neuron activity and highlight the considerable potential of TAFA4 as a treatment for injury-induced mechanical pain.

摘要

疼痛，无论是急性还是慢性，都是全球范围内严重的医学问题。然而，其管理仍然不尽如人意，需要新的镇痛分子。我们在这里表明，TAFA4 逆转了雄性和雌性小鼠的炎症、术后和 spared 神经损伤（SNI）引起的机械性敏感性。TAFA4 需要功能性低密度脂蛋白受体相关蛋白（LRPs），因为它们的抑制剂 RAP（受体相关蛋白）剂量依赖性地消除其抗敏感性作用。SNI 选择性地减少脊髓层 II 外兴奋性中间神经元（L-IIo ExINs）中的 A 型钾电流（I），并诱导层 II 内抑制性中间神经元（L-IIi InhINs）中的 I 增加和 hyperpolarization-activated current（I）减少。值得注意的是，SNI 诱导的这两种 IN 亚型的离子电流变化均通过 LRP 依赖性方式被 TAFA4 挽救。我们深入了解了 TAFA4 通过恢复正常脊髓神经元活动来逆转损伤诱导的机械性敏感性的机制，并强调了 TAFA4 作为治疗损伤诱导的机械性疼痛的巨大潜力。