Both preclinical models, human genetics and physiology demonstrate that hyperexcitability in sensory neurons is a key driver of the maladaptive changes associated with persistent pain. Such hyper-excitability is a treatment target with a number of ion channel targets currently in development but selectivity can be an issue. Chemogenetics has shown promise as a means to suppress neuronal 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. I will discuss how this channel can be used in silencing both mouse and human sensory neurons. Virally mediated expression of PSAM4-GlyR in mouse sensory neurons produced behavioral hyposensitivity upon agonist administration and stable expression of the channel led to similar suppression of pain-related behavior 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 this could ameliorate models of persistent pain. Effective silencing of behavioral 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. This 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. It also enables dissection of the contribution of different primary afferent populations to persistent pain.
David is Professor of neurology and neurobiology at the University of Oxford and consultant neurologist at Oxford University Hospitals in the UK. He is head of the Division of Clinical Neurology at the University of Oxford and a senior research fellow of Green Templeton College. His research focus is to understand the pathogenesis of neural injury and neuropathic pain and ultimately improve the clinical management of this debilitating condition. He takes a translational approach ranging from cell based models to human psychophysics and clinical cohorts. He administers a specialist neuropathic pain clinic based at Oxford University hospitals. He has led the identification of novel clinical neuropathies and inherited pain channelopathies. He leads major international and national consortia including DOLORisk and PAINSTORM investigating risk factors and determinants of neuropathic pain. He received the PD Wall medal from the Royal College of Anaesthetists in 2016 and became an honorary Skou professor of Aarhus University in 2019. He was appointed to Fellowship if the Academy of Medical Sciences in 2020 for excellence in pain research.