학술논문
A humanized chemogenetic system inhibits murine pain-related behavior and hyperactivity in human sensory neurons.
Document Type
Academic Journal
Author
Perez-Sanchez J; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.; Middleton SJ; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.; Pattison LA; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.; Hilton H; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.; Ali Awadelkareem M; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.; Zuberi SR; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.; Renke MB; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.; Hu H; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.; Yang X; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.; Clark AJ; Blizard Institute, Barts and the London School of Medicine and Dentistry, London E1 2AT, UK.; St John Smith E; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.; Bennett DL; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
Source
Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE
Subject
Language
English
Abstract
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. PSAM 4 -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 PSAM 4 -GlyR in mouse sensory neurons produced behavioral hyposensitivity upon agonist administration, which was recovered upon agonist washout. Stable expression of the channel led to similar reversible suppression of pain-related behavior even after 10 months of viral delivery. Mechanical and spontaneous pain readouts were also ameliorated by PSAM 4 -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 behavioral hypersensitivity was reproduced in a human model of hyperexcitability and clinical pain: PSAM 4 -GlyR activation decreased the excitability of human-induced pluripotent stem cell-derived sensory neurons and spontaneous activity due to a gain-of-function Na V 1.7 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.