Pain-sensing sensory neurons of the dorsal root ganglion (DRG) can become sensitized (hyperexcitable) in response to surgically-induced peripheral tissue injury. However, the potential role and molecular mechanisms of nociceptive ion channel dysregulation in acute pain conditions such as those resulting from skin and soft tissue incision remain unknown. Here, we use selective pharmacology, electrophysiology and mouse genetics to link observed increased current densities arising from Ca v3.2 isoform of T-type calcium channels (T-channels) to nociceptive sensitization using a clinically-relevant rodent model of skin and deep tissue incision. Furthermore, knockdown of the Ca v3.2-targeting deubiquitinating enzyme USP5, or the specific disruption of its binding to Ca v3.2 channel, in peripheral nociceptors resulted in a robust antihyperalgesic effect in vivo, and substantial T-current reduction in vitro. Our study provides a key mechanistic understanding of Ca v3.2 channel’s plasticity post-surgical incision and identifies novel therapies for perioperative pain that may greatly decrease the need for narcotics and potential for drug abuse.
Selective pharmacological antagonism of Ca v3.2 channels in peripheral nociceptors and disruption of Ca v3.2-USP5 signaling alleviate hyperalgesia post-surgery.