The scientists from Nuffield Department of Clinical Neurosciences assessed if a tailored pain treatment approach could involve directly inhibiting pain-related hyperactivity in sensory neurons. Indeed, they have now shown that there is a chemogenetic approach that is suitable for human applications. Chemogenetics is the engineering of molecules that regulate neuronal excitation (stimulation) so that the molecules only become active in the presence of a non-toxic drug. In animal studies, this procedure has already demonstrated promise in reducing such excitability.
Using mouse sensory neurons, the group first expressed the gene PSAM4-GlyR, which is a chemogenetic system based on the human glycine and nicotinic receptors acetylcholine. By using the clinically approved drug varenicline to activate PSAM4-GlyR, they were able to suppress sensory neurons and lessen the pain hypersensitivity that is typically linked to arthritis or nerve injury in mice. Then, the researchers went on to activate the PSAM4-GlyR system in sensory neurons taken from a patient who had erythromelalgia, a disorder marked by searing pain. They found that this inhibited the neurons and restored hyperactivity.
Although more validation in human pain models is required, the researchers have demonstrated the translational potential of engineering human protein receptors for the treatment of pain, as the results show that persistent pain resulting from arthritis or nervous system injury is partly caused by sensory neuron hyperexcitability.
Reference: Perez-Sanchez J, Middleton SJ, Pattison LA, et al. A humanized chemogenetic system inhibits murine pain-related behavior and hyperactivity in human sensory neurons. Sci Transl Med. 2023;15(716):eadh3839. doi: 10.1126/scitranslmed.adh3839