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Selective inhibition of CaV3.2 channels reverses hyperexcitability of peripheral nociceptors and alleviates postsurgical pain
Science Signaling ( IF 6.7 ) Pub Date : 2018-08-28 , DOI: 10.1126/scisignal.aao4425
Sonja L. Joksimovic 1, 2 , Srdjan M. Joksimovic 1 , Vesna Tesic 1 , Agustin García-Caballero 3 , Simon Feseha 1 , Gerald W. Zamponi 3 , Vesna Jevtovic-Todorovic 1 , Slobodan M. Todorovic 1, 4
Affiliation  

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.



中文翻译:

CaV3.2通道的选择性抑制可逆转周围伤害感受器的过度兴奋性并减轻术后疼痛

响应手术引起的周围组织损伤,背根神经节(DRG)的疼痛感官感觉神经元可能变得敏感或过度兴奋。我们调查了伤害性离子通道失调在诸如皮肤和软组织切口引起的急性疼痛情况下的潜在作用和分子机制。我们使用临床相关的啮齿类动物皮肤和深部组织切口模型,通过选择性药理学,电生理学和小鼠遗传学,将由T型钙通道(T通道)的Ca V 3.2亚型引起的增加的电流密度与伤害性敏化联系起来。此外,击倒靶向Ca V 3.2的去泛素化酶USP5或破坏USP5与Ca V的结合周围伤害感受器中的3.2通道在体内产生了强大的抗痛觉过敏作用,并在体外显着降低了T电流。我们的研究为可塑性在手术切口后在Ca V 3.2通道活动中的作用提供了机械方面的见解,并确定了围手术期疼痛的潜在目标,这些目标可能会大大减少对麻醉品的需求和吸毒的可能性。

更新日期:2018-08-29
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