Pain-sensing sensory neurons of the dorsal root ganglion (DRG) can become sensitized or hyperexcitable in response to surgically induced peripheral tissue injury. We investigated 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. We used selective pharmacology, electrophysiology, and mouse genetics to link increased current densities arising from the Ca3.2 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 Ca3.2-targeting deubiquitinating enzyme USP5 or disruption of USP5 binding to Ca3.2 channels in peripheral nociceptors resulted in a robust antihyperalgesic effect in vivo and substantial T-current reduction in vitro. Our study provides mechanistic insight into the role of plasticity in Ca3.2 channel activity after surgical incision and identifies potential targets for perioperative pain that may greatly decrease the need for narcotics and potential for drug abuse.

Several studies suggest that voltage-gated calcium currents are involved in generating high frequency burst firing in the subiculum, but the exact nature of these currents remains unknown. Here, we used selective pharmacology, molecular and genetic approaches to implicate Cav3.1-containing T-channels in subicular burst firing, in contrast to several previous reports discounting T-channels as major contributors to subicular neuron physiology. Furthermore, pharmacological antagonism of T-channels, as well as global deletion of CaV3.1 isoform, completely suppressed development of long-term potentiation (LTP) in the CA1-subiculum, but not in the CA3-CA1 pathway. Our results indicate that excitability and synaptic plasticity of subicular neurons relies heavily on T-channels. Hence, T-channels may be a promising new drug target for different cognitive deficits.

Background and Purpose Neuroactive steroid (3β,5β,17β)‐3‐hydroxyandrostane‐17‐carbonitrile (3β‐OH) is a novel hypnotic and voltage‐dependent blocker of T‐type calcium channels. Here, we examine its potential analgesic effects and adjuvant anaesthetic properties using a post‐surgical pain model in rodents. Experimental Approach Analgesic properties of 3β‐OH were investigated in thermal and mechanical nociceptive tests in sham or surgically incised rats and mice, with drug injected either systemically (intraperitoneal) or locally via intrathecal or intraplantar routes. Hypnotic properties of 3β‐OH and its use as an adjuvant anaesthetic in combination with isoflurane were investigated using behavioural experiments and in vivo EEG recordings in adolescent rats. Key Results A combination of 1% isoflurane with 3β‐OH (60 mg·kg−1, i.p.) induced suppression of cortical EEG and stronger thermal and mechanical anti‐hyperalgesia during 3 days post‐surgery, when compared to isoflurane alone and isoflurane with morphine. 3β‐OH exerted prominent enantioselective thermal and mechanical antinociception in healthy rats and reduced T‐channel‐dependent excitability of primary sensory neurons. Intrathecal injection of 3β‐OH alleviated mechanical hyperalgesia, while repeated intraplantar application alleviated both thermal and mechanical hyperalgesia in the rats after incision. Using mouse genetics, we found that CaV3.2 T‐calcium channels are important for anti‐hyperalgesic effect of 3β‐OH and are contributing to its hypnotic effect. Conclusion and Implications Our study identifies 3β‐OH as a novel analgesic for surgical procedures. 3β‐OH can be used to reduce T‐channel‐dependent excitability of peripheral sensory neurons as an adjuvant for induction and maintenance of general anaesthesia while improving analgesia and lowering the amount of volatile anaesthetic needed for surgery.