Patel R, Rutten K, Valdor M, Schiene K, Wigge S, Schunk S, Damann N, Christoph T, Dickenson A H
University College London, Gower Street, Department of Neuroscience, Physiology and Pharmacology, London WC1E 6BT, UK.
Grünenthal GmbH, Global Preclinical Research, 52078 Aachen, Germany.
Neuroscience. 2015 Jun 25;297:47-57. doi: 10.1016/j.neuroscience.2015.03.057. Epub 2015 Apr 1.
Prialt, a synthetic version of Ca(v)2.2 antagonist ω-conotoxin MVIIA derived from Conus magus, is the first clinically approved voltage-gated calcium channel blocker for refractory chronic pain. However, due to the narrow therapeutic window and considerable side effects associated with systemic dosing, Prialt is only administered intrathecally. N-triazole oxindole (TROX-1) is a novel use-dependent and activation state-selective small-molecule inhibitor of Ca(v)2.1, 2.2 and 2.3 calcium channels designed to overcome the limitations of Prialt. We have examined the neurophysiological and behavioral effects of blocking calcium channels with TROX-1. In vitro, TROX-1, in contrast to state-independent antagonist Prialt, preferentially inhibits Ca(v)2.2 currents in rat dorsal root ganglia (DRG) neurons under depolarized conditions. In vivo electrophysiology was performed to record from deep dorsal horn lamina V/VI wide dynamic range neurons in non-sentient spinal nerve-ligated (SNL) and sham-operated rats. In SNL rats, spinal neurons exhibited reduced responses to innocuous and noxious punctate mechanical stimulation of the receptive field following subcutaneous administration of TROX-1, an effect that was absent in sham-operated animals. No effect was observed on neuronal responses evoked by dynamic brushing, heat or cold stimulation in SNL or sham rats. The wind-up response of spinal neurons following repeated electrical stimulation of the receptive field was also unaffected. Spinally applied TROX-1 dose dependently inhibited mechanically evoked neuronal responses in SNL but not sham-operated rats, consistent with behavioral observations. This study confirms the pathological state-dependent actions of TROX-1 through a likely spinal mechanism and reveals a modality selective change in calcium channel function following nerve injury.
普瑞巴林（Prialt）是一种合成的Ca(v)2.2拮抗剂ω-芋螺毒素MVIIA，源自芋螺，是首个临床批准用于难治性慢性疼痛的电压门控钙通道阻滞剂。然而，由于治疗窗狭窄以及全身给药相关的显著副作用，普瑞巴林仅通过鞘内给药。N-三唑吲哚酮（TROX-1）是一种新型的依赖于使用情况且具有激活状态选择性的小分子Ca(v)2.1、2.2和2.3钙通道抑制剂，旨在克服普瑞巴林的局限性。我们研究了TROX-1阻断钙通道的神经生理和行为学效应。在体外，与非状态依赖性拮抗剂普瑞巴林不同，TROX-1在去极化条件下优先抑制大鼠背根神经节（DRG）神经元中的Ca(v)2.2电流。进行体内电生理记录，以记录非感觉性脊髓神经结扎（SNL）和假手术大鼠深部背角V/VI层宽动态范围神经元的活动。在SNL大鼠中，皮下注射TROX-1后，脊髓神经元对感受野无害和有害点状机械刺激的反应减弱，而假手术动物中未观察到这种效应。在SNL或假手术大鼠中，动态刷擦、热或冷刺激诱发的神经元反应未受影响。感受野重复电刺激后脊髓神经元的wind-up反应也未受影响。脊髓应用TROX-1剂量依赖性地抑制SNL大鼠而非假手术大鼠中机械诱发的神经元反应，这与行为学观察结果一致。本研究通过可能的脊髓机制证实了TROX-1的病理状态依赖性作用，并揭示了神经损伤后钙通道功能的模式选择性变化。
