Editor’s summary
The current opioid crisis emphasizes the need for nonaddictive pain treatments. Here Perez-Sanchez and colleagues evaluated whether direct inhibition of pain-related hyperactivity in sensory neurons could be such a targeted pain treatment strategy. The authors expressed PSAM4-GlyR, a chemogenetic system based on the human nicotinic acetylcholine and glycine receptors, in mouse sensory neurons. PSAM4-GlyR activation with the FDA-approved drug varenicline inhibited sensory neurons and improved acute, inflammatory, and neuropathic pain-related behaviors in mice. PSAM4-GlyR activation also inhibited human-derived sensory neurons and normalized hyperactivity in sensory neurons derived from a patient with erythromelalgia, a condition characterized by burning pain. Although further validation in human pain models is needed, these results suggest the potential of PSAM4-GlyR in gene therapy for pain treatment. —Daniela Neuhofer
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. 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. 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 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 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. 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.
