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Sustained relief of ongoing experimental neuropathic pain by a CRMP2 peptide aptamer with low abuse potential

机译：低滥用潜力的CRMP2肽适体可持续缓解正在进行的实验性神经性疼痛

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摘要

Uncoupling the protein-protein interaction between collapsin response mediator protein 2 (CRMP2) and N-type voltage-gated calcium channel (CaV2.2) with an allosteric CRMP2-derived peptide (CBD3) is antinociceptive in rodent models of inflammatory and neuropathic pain. We investigated the efficacy, duration of action, abuse potential, and neurobehavioral toxicity of an improved mutant CRMP2 peptide. A homopolyarginine (R9)-conjugated CBD3-A6K (R9-CBD3-A6K) peptide inhibited the CaV2.2-CRMP2 interaction in a concentration-dependent fashion and diminished surface expression of CaV2.2 and depolarization-evoked Ca2+ influx in rat dorsal root ganglia neurons. In vitro studies demonstrated suppression of excitability of small-to-medium diameter dorsal root ganglion and inhibition of subtypes of voltage-gated Ca2+ channels. Sprague-Dawley rats with tibial nerve injury had profound and long-lasting tactile allodynia and ongoing pain. Immediate administration of R9-CBD3-A6K produced enhanced dopamine release from the nucleus accumbens shell selectively in injured animals, consistent with relief of ongoing pain. R9-CBD3-A6K, when administered repeatedly into the central nervous system ventricles of naive rats, did not result in a positive conditioned place preference demonstrating a lack of abusive liability. Continuous subcutaneous infusion of R9-CBD3-A6K over a 24- to 72-hour period reversed tactile allodynia and ongoing pain, demonstrating a lack of tolerance over this time course. Importantly, continuous infusion of R9-CBD3-A6K did not affect motor activity, anxiety, depression, or memory and learning. Collectively, these results validate the potential therapeutic significance of targeting the CaV-CRMP2 axis for treatment of neuropathic pain.
机译：在炎症性和神经性疼痛的啮齿动物模型中，将胶原蛋白应答蛋白2（CRMP2）和N型电压门控钙通道（CaV2.2）与别构CRMP2衍生肽（CBD3）之间的蛋白相互作用相互作用是抗伤害感受的。我们调查了改进的突变体CRMP2肽的功效，作用时间，潜在滥用和神经行为毒性。高聚精氨酸（R9）偶联的CBD3-A6K（R9-CBD3-A6K）肽以浓度依赖的方式抑制CaV2.2-CRMP2相互作用，并减少CaV2.2的表面表达和去极化诱发的Ca2 +流入大鼠背根。神经节神经元。体外研究表明，中小直径背根神经节的兴奋性受到抑制，电压门控Ca2 +通道的亚型受到抑制。患有胫神经神经损伤的Sprague-Dawley大鼠具有深远的触觉异常性疼痛和持续疼痛。在受伤的动物中，立即施用R9-CBD3-A6K可以使伏隔核壳中的多巴胺选择性释放，从而减轻了持续疼痛。将R9-CBD3-A6K反复施用于幼稚大鼠的中枢神经系统脑室时，不会导致出现条件性位置偏爱的阳性现象，这表明缺乏滥用的能力。在24到72小时内连续皮下输注R9-CBD3-A6K可逆转触觉异常性疼痛和持续疼痛，这表明在这段时间内缺乏耐受性。重要的是，连续输注R9-CBD3-A6K不会影响运动活动，焦虑，抑郁或记忆和学习。总体而言，这些结果验证了靶向CaV-CRMP2轴治疗神经性疼痛的潜在治疗意义。

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