Uncovering a new route to pain therapy

High-voltage-activated calcium channels (HVACCs) are promising targets for developing analgesics given their roles in controlling synaptic transmission, neuronal excitability and neuropeptide release in primary nociceptive neurons. Despite previous efforts in developing HVACCs inhibitors of various drug modalities, it remains undetermined whether targeting HVACCs directly by a gene therapy approach could lead to pain alleviation in vivo. To test this, Sun and colleagues adopted a post-translational ubiquitination-based knockdown method targeting HVACCs in primary sensory neurons. They showed ablation of HVACC currents in a subset of primary sensory neurons, dampened hyperexcitability of sensory neurons after nerve injury and reduced pain behavior with no apparent adverse effects [1]. The results open the possibility of targeting ion channels with ubiquitination-based knockdown as a promising gene therapy candidate for pain treatment in future clinical studies.