A humanized chemogenetic system inhibits murine pain-related behavior and hyperactivity in human sensory neurons.
A humanized chemogenetic system inhibits murine pain-related behavior and hyperactivity in human sensory neurons.
复制标题
DOI：
10.1126/scitranslmed.adh3839
复制
发表时间：
2023-10-04
影响因子：
17.1
通讯作者：
Bennett DL
中科院分区：
文献类型：
--
作者：
Perez-Sanchez J;Middleton SJ;Pattison LA;Hilton H;Ali Awadelkareem M;Zuberi SR;Renke MB;Hu H;Yang X;Clark AJ;St John Smith E;Bennett DL
已知感觉神经元的过度兴奋是许多与持续性疼痛相关的适应不良变化的基础。化学遗传学已显示出作为抑制这种兴奋性的手段的希望，但需要适合于人类应用的化学遗传学方法。PSAM 4-GlyR是基于人α7烟碱乙酰胆碱和甘氨酸受体的模块化系统，其响应于惰性化学配体和临床批准的药物伐尼克兰。在这里，我们证明了该通道在沉默小鼠和人的感觉神经元激动剂给药后，通过激活大的分流电导的功效。小鼠感觉神经元中病毒介导的PSAM 4-GlyR表达在激动剂施用后产生行为低敏感性，其在激动剂洗脱后恢复。重要的是，即使在病毒递送10个月后，通道的稳定表达也导致疼痛相关行为的类似可逆抑制。在急性和关节疼痛炎症小鼠模型中，PSAM 4-GlyR活化也改善了机械和自发性疼痛读数。此外，在激活该通道后，还观察到对由神经性疼痛的备用神经损伤模型产生的机械超敏反应的抑制。在过度兴奋和临床疼痛的人类模型中再现了行为超敏反应的有效沉默：PSAM 4-GlyR激活降低了人类诱导多能干细胞衍生的感觉神经元的兴奋性和自发活动，这是由于功能获得NaV1.7突变引起遗传性红斑性肢痛症。我们的研究结果表明，感觉神经元的过度兴奋性的神经性疼痛和翻译潜力的一个有效的，稳定的和可逆的人源化化学系统治疗疼痛的贡献。
Hyperexcitability in sensory neurons is known to underlie many of the maladaptive changes associated with persistent pain. Chemogenetics has shown promise as a means to suppress such excitability, yet chemogenetic approaches suitable for human applications are needed. PSAM4-GlyR is a modular system based on the human α7 nicotinic acetylcholine and glycine receptors, which responds to inert chemical ligands and the clinically approved drug, varenicline. Here, we demonstrated the efficacy of this channel in silencing both mouse and human sensory neurons by the activation of large shunting conductances after agonist administration. Virally mediated expression of PSAM4-GlyR in mouse sensory neurons produced behavioral hyposensitivity upon agonist administration, which was recovered upon agonist washout. Importantly, stable expression of the channel led to similar reversible suppression of pain related behaviour even after 10 months of viral delivery. Mechanical and spontaneous pain readouts were also ameliorated by PSAM4-GlyR activation in acute and joint pain inflammation mouse models. Furthermore, suppression of mechanical hypersensitivity generated by a spared nerve injury model of neuropathic pain was also observed upon activation of the channel. Effective silencing of behavioural hypersensitivity was reproduced in a human model of hyperexcitability and clinical pain: PSAM4-GlyR activation decreased the excitability of human induced pluripotent stem-cell-derived sensory neurons and spontaneous activity due to a gain of function NaV1.7 mutation causing inherited erythromelalgia. Our results demonstrate the contribution of sensory neuron hyperexcitability to neuropathic pain and the translational potential of an effective, stable and reversible humanized chemogenetic system for the treatment of pain.
登录
查看更多内容
影响因子：
5.3
作者：
通讯作者：
--
影响因子：
16.2
作者：
Chen, Xinhong;Kumar, Sripriya Ravindra;Adams, Cameron D.;Yang, Daping;Wang, Tongtong;Wolfe, Damien A.;Arokiaraj, Cynthia M.;Ngo, Victoria;Campos, Lillian J.;Griffiths, Jessica A.;Ichiki, Takako;Mazmanian, Sarkis K.;Osborne, Peregrine B.;Keast, Janet R.;Miller, Cory T.;Fox, Andrew S.;Chiu, Isaac M.;Gradinaru, Viviana
通讯作者：
Gradinaru, Viviana
影响因子：
5.2
作者：
Bardoni R;Takazawa T;Tong CK;Choudhury P;Scherrer G;Macdermott AB
通讯作者：
Macdermott AB
影响因子：
14.5
作者：
Alsaloum, Matthew;Labau, Julie I. R.;Waxman, Stephen G.
通讯作者：
Waxman, Stephen G.
影响因子：
25
作者：
Chan KY;Jang MJ;Yoo BB;Greenbaum A;Ravi N;Wu WL;Sánchez-Guardado L;Lois C;Mazmanian SK;Deverman BE;Gradinaru V
通讯作者：
Gradinaru V