Targeted ubiquitination of sensory neuron calcium channels reduces the development of neuropathic pain

Significance Neuropathic pain affects nearly 10% of the US population, and yet current treatments with small-molecule drugs fail to adequately alleviate nociception and often produce serious side effects. High-voltage-activated calcium channels (HVACCs) are membrane proteins that are necessary for synaptic transmission in sensory neurons, and inhibiting these channels is a proven method to achieve analgesia. In this work, we used subcutaneous injection to express a genetically encoded molecule that blocks HVACCs in sensory neurons in vivo. We demonstrate that this approach effectively reduces the onset of neuropathic pain in an animal model of the disease without any observable side effects. These studies support the development of a gene therapy targeting the inhibition of HVACCs to preempt, and potentially reverse, neuropathic pain.