Research ArticleNeuroscience

Selective inhibition of CaV3.2 channels reverses hyperexcitability of peripheral nociceptors and alleviates postsurgical pain

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Sci. Signal.  28 Aug 2018:
Vol. 11, Issue 545, eaao4425
DOI: 10.1126/scisignal.aao4425

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Preventing postsurgical pain

Opiate abuse has necessitated finding alternative therapeutic targets to alleviate postsurgical pain. The Ca2+ channel CaV3.2 has been implicated in inflammatory and neuropathic pain. Joksimovic et al. now show that postsurgical pain also triggers CaV3.2 channel activity by increasing its stability at the surface of pain-sensing neurons. In rodents, pharmacologically inhibiting CaV3.2 or preventing the deubiquitinating enzyme USP5 from stabilizing the channel reversed postoperative hypersensitivity to mechanical and heat stimuli, pain syndromes that are also typical in patients after surgery. Targeting CaV3.2 or the ability of USP5 to bind to the channel may provide a strategy for relieving postsurgical pain that lacks the addiction potential of opiates.

Abstract

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 CaV3.2 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 CaV3.2-targeting deubiquitinating enzyme USP5 or disruption of USP5 binding to CaV3.2 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 CaV3.2 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.

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