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Targeting spinal mechanistic target of rapamycin complex 2 alleviates inflammatory and neuropathic pain
Brain ( IF 10.6 ) Pub Date : 2024-08-20 , DOI: 10.1093/brain/awae275
Calvin Wong 1 , Luis David Rodriguez-Hernandez 2 , Kevin C Lister 1 , Ning Gu 1 , Weihua Cai 1 , Mehdi Hooshmandi 1 , Jonathan Fan 1 , Nicole Brown 1 , Vivienne Nguyen 1 , Alfredo Ribeiro-da-Silva 3, 4, 5 , Robert P Bonin 2, 6 , Arkady Khoutorsky 1, 5, 7
Affiliation  

The development and maintenance of chronic pain involve the reorganization of spinal nocioceptive circuits. The mechanistic target of rapamycin complex 2 (mTORC2), a central signalling hub that modulates both actin-dependent structural changes and mechanistic target of rapamycin complex 1 (mTORC1)-dependent mRNA translation, plays key roles in hippocampal synaptic plasticity and memory formation. However, its function in spinal plasticity and chronic pain is poorly understood. Here, we show that pharmacological activation of spinal mTORC2 induces pain hypersensitivity, whereas its inhibition, using downregulation of the mTORC2-defining component Rictor, alleviates both inflammatory and neuropathic pain. Cell type-specific deletion of Rictor showed that the selective inhibition of mTORC2 in a subset of excitatory neurons impairs spinal synaptic potentiation and alleviates inflammation-induced mechanical and thermal hypersensitivity and nerve injury-induced heat hyperalgesia. The ablation of mTORC2 in inhibitory interneurons strongly alleviated nerve injury-induced mechanical hypersensitivity. Our findings reveal the role of mTORC2 in chronic pain and highlight its cell type-specific functions in mediating pain hypersensitivity in response to peripheral inflammation and nerve injury.

中文翻译:


雷帕霉素复合物 2 的靶向脊柱机制靶点可缓解炎症和神经性疼痛



慢性疼痛的发展和维持涉及脊髓伤害感受回路的重组。雷帕霉素复合物 2 (mTORC2) 的机制靶点是调节肌动蛋白依赖性结构变化的中央信号枢纽和雷帕霉素复合物 1 (mTORC1) 依赖性 mRNA 翻译的机制靶点,在海马突触可塑性和记忆形成中起关键作用。然而,它在脊柱可塑性和慢性疼痛中的功能知之甚少。在这里,我们表明脊髓 mTORC2 的药理学激活会诱导疼痛超敏反应,而其抑制使用 mTORC2 定义成分 Rictor 的下调,减轻炎症和神经性疼痛。Rictor 的细胞类型特异性缺失表明,在兴奋性神经元子集中 mTORC2 的选择性抑制损害了脊髓突触增强,并减轻了炎症诱导的机械和热超敏反应以及神经损伤诱导的热痛觉过敏。抑制性中间神经元中 mTORC2 的消融强烈减轻了神经损伤诱导的机械超敏反应。我们的研究结果揭示了 mTORC2 在慢性疼痛中的作用,并强调了其细胞类型特异性功能在介导响应外周炎症和神经损伤的疼痛超敏反应中的作用。
更新日期:2024-08-20
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