(S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology.
(S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology.
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DOI：
10.1097/j.pain.0000000000000555
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发表时间：
2016-07
期刊：
影响因子：
7.4
通讯作者：
Khanna R
中科院分区：
文献类型：
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作者：
Moutal A;Chew LA;Yang X;Wang Y;Yeon SK;Telemi E;Meroueh S;Park KD;Shrinivasan R;Gilbraith KB;Qu C;Xie JY;Patwardhan A;Vanderah TW;Khanna M;Porreca F;Khanna R
慢性疼痛影响着数百万人的生活。目前的治疗方法都有有害的副作用。我们提出了一种靶向调节N型电压门控钙(CaV2)的蛋白质相互作用的策略。2)通道作为直接通道阻塞的替代方案。解偶联CaV2的多肽。2与轴突塌陷反应介体蛋白2(CRMP2)的相互作用是抗伤害性的，对记忆、抑郁和奖赏/成瘾没有影响。寻找可以概括CaV2解偶联的小分子。2-CRMP2相互作用鉴定(S)-乳糖胺[(S)-乳糖胺]，食品和药物管理局批准的抗癫痫药物(R)-乳糖胺[(R)-LCM，Vimpat]的非活性对映体。我们发现，(S)-LCM，而不是(R)-LCM，抑制了细胞周期蛋白依赖性激酶5对CRMP2的磷酸化，这是驱动CaV2所必需的步骤。S)-乳糖胺以低微摩尔IC50抑制去极化诱导的Ca21内流。电压钳电生理实验表明，急性应用(S)-LCM后，感觉神经元Ca21电流相应减少。利用星座药理学，一个最近被描述的高含量的神经元功能指纹表型筛选平台，使用亚型选择性药理学药物来阐明定义特定细胞类型的关键信号蛋白的细胞特异性组合(星座)，我们研究了(S)-LCM是否优先作用于某些类型的神经元。(S)-乳糖胺减少了对芥子油的反应的背根节神经元，增加了对薄荷脑反应的细胞数量。最后，(S)-LCM逆转了一个术后疼痛模型和两个神经病理性疼痛模型中的热过敏和机械超敏。因此，使用(S)-LCM抑制CRMP2的磷酸化是一种新颖而有效的治疗疼痛的策略，该策略通过靶向特定的感觉神经元群体发挥作用。
Chronic pain affects the life of millions of people. Current treatments have deleterious side effects. We have advanced a strategy for targeting protein interactions which regulate the N-type voltage-gated calcium (CaV2. 2) channel as an alternative to direct channel block. Peptides uncoupling CaV2. 2 interactions with the axonal collapsin response mediator protein 2 (CRMP2) were antinociceptive without effects on memory, depression, and reward/addiction. A search for small molecules that could recapitulate uncoupling of the CaV2. 2–CRMP2 interaction identified (S)-lacosamide [(S)-LCM], the inactive enantiomer of the Food and Drug Administration–approved antiepileptic drug (R)-lacosamide [(R)-LCM, Vimpat]. We show that (S)-LCM, but not (R)-LCM, inhibits CRMP2 phosphorylation by cyclin dependent kinase 5, a step necessary for driving CaV2. 2 activity, in sensory neurons.(S)-lacosamide inhibited depolarization-induced Ca21 influx with a low micromolar IC50. Voltage-clamp electrophysiology experiments demonstrated a commensurate reduction in Ca21 currents in sensory neurons after an acute application of (S)-LCM. Using constellation pharmacology, a recently described high content phenotypic screening platform for functional fingerprinting of neurons that uses subtype-selective pharmacological agents to elucidate cell-specific combinations (constellations) of key signaling proteins that define specific cell types, we investigated if (S)-LCM preferentially acts on certain types of neurons.(S)-lacosamide decreased the dorsal root ganglion neurons responding to mustard oil, and increased the number of cells responding to menthol. Finally,(S)-LCM reversed thermal hypersensitivity and mechanical allodynia in a model of postoperative pain, and 2 models of neuropathic pain. Thus, using (S)-LCM to inhibit CRMP2 phosphorylation is a novel and efficient strategy to treat pain, which works by targeting specific sensory neuron populations.