Sodium Channel Nav1.6 in Chemotherapy-Induced Pain

在过去的十年里，我们的多学科研究结合了分子遗传学、细胞生物学、离子通道 生物物理学、感觉神经元生理学和行为分析已经明确了钠通道的作用 NAV1.6在疼痛中。我们现在的目标是研究NaV1.6在化疗引起的疼痛和 周围神经病(CIPPN)，并确定Nav1.6的遗传变异是否会影响 化疗药物介导的疼痛敏感性。这些研究将为疼痛的治疗选择提供信息 以及个性化的、基于药物基因组学的策略，为癌症患者开出化疗处方。 化疗常常与钠离子通道病和神经病变的发展有关。 此外，有关NAV1.6与CIPPN有关的研究表明，DRG中持续和复苏的电流增强 化疗药物奥沙利铂治疗后的神经元。我们实验室最近的工作是 提示Nav1.6参与了另一种化疗药物长春新碱引起的疼痛。然而， 长春新碱诱导疼痛(VIP)的病理生理学和药理学，包括潜在的遗传风险 目前尚不清楚这些因素。我们在这份提案中的目标是调查Nav1.6--行动的基本渠道 在有髓纤维中的潜在传播-在CIPPN中：a)确定Nav1.6在VIP中的作用；b)告知 以药物基因组学为基础的化疗以避免CIPPN的发展；以及c)开发一种新的非阿片类药物 以Nav1.6为目标的基于治疗策略 我们将采用以下研究设计和方法来实现我们的目标。 具体目标1：在体内评估Nav1.6对VIP的贡献。我们从胚胎开始的初步数据 对Nav1.6的基因敲除研究表明，这一渠道对VIP有贡献。然而，有可能 补偿机制可能会混淆观察到的结果。在这里，我们将在成年小鼠中敲除Nav1.6以 评估以下能更好地为未来成人受试者的翻译研究提供信息的指标。 具体目标2：评估NA1.6基因变异是否为VIP的危险因素。并不是所有的患者都经历了 化疗导致CIPPN，这表明基因变异可能是夸大反应的基础 化疗。我们的实验室是第一个证明Nav1.6的功能增益(GOF)变体可以导致 癫痫，一种类似神经病理性疼痛的疾病，反映潜在的神经元过度兴奋。我们有 最近还在一名疼痛的三叉神经痛患者中发现了NaV1.6(Met136Val)的GOF变体， 这表明该变异可能使携带者更容易发生疾病。NaV1.6-M136V 通道增加了瞬时和复活电流的幅度，增加了神经元的放电。在这一特定情况下 目的研究NaV1.6-M136V对小鼠血管内皮细胞炎性病变的影响。 具体目标3：评估使用大麻类药物改善VIP的情况。大麻二醇(CBD)是FDA批准的 用于治疗某些形式的癫痫，并已被证明可在 避免峰值瞬时电流的浓度，并降低神经元的兴奋性。在这一具体目标中，我们 将决定使用CBD治疗是否能改善VIP。我们还会将CBD的影响与 FDA批准的度洛西汀(Cymbalta®)，具有钠通道阻断活性，已被证明是 对治疗CIPPN有效。

Over the past decade, our multi-disciplinary studies combining molecular genetics, cell biology, ion channel biophysics, sensory neuron physiology, and behavioral analysis have pinpointed the role of sodium channel NaV1.6 in pain. Our goal now is to investigate the contribution of NaV1.6 to chemotherapy-induced pain and peripheral neuropathy (CIPPN), and to determine whether genetic variants of Nav1.6 can influence susceptibility to pain mediated by chemotherapeutic drugs. These studies will inform treatment options for pain and personalized, pharmacogenomics-based strategies in prescribing chemotherapy to cancer patients. Chemotherapy is frequently associated with sodium channelopathy and the development of neuropathy. Furthermore, studies implicating NaV1.6 in CIPPN show enhanced persistent and resurgent currents in DRG neurons following treatment with the chemotherapeutic agent oxaliplatin. Recent work from our lab has suggested involvement of Nav1.6 in pain induced by vincristine, another chemotherapeutic agent. However, the pathophysiology and pharmacology of vincristine-induced pain (VIP) including underlying genetic risk factors remain unclear. Our goal in this proposal is to investigate Nav1.6—an essential channel for action potential propagation in myelinated fibers—in CIPPN to: a) Establish the role of Nav1.6 in VIP; b) Inform pharmacogenomics-based chemotherapy to avert development of CIPPN; and c) Develop a novel non-opioid based treatment strategy that targets Nav1.6 We will apply the following research design and methods to achieve our goal. Specific Aim 1: Assess the contribution of Nav1.6 to VIP in vivo. Our preliminary data from embryonic knockout studies of Nav1.6 suggests a contribution by this channel to VIP. However, it is possible that compensatory mechanisms may confound observed outcomes. Here, we will knockout Nav1.6 in adult mice to assess the following metrics that can better inform future translational studies in adult subjects. Specific Aim 2: Assess genetic variations in Nav1.6 as a risk factor for VIP. Not all patients who undergo chemotherapy develop CIPPN, which suggests that genetic variations may underlie exaggerated response to chemotherapy. Our laboratory was the first to show that gain-of-function (GOF) variants of Nav1.6 can cause epilepsy, a disorder similar to neuropathic pain that reflects underlying neuronal hyperexcitability. We have also recently identified a GOF variant in NaV1.6 (Met136Val) in a patient with painful trigeminal neuralgia, which suggests that this variant may predispose the carrier to the development of disease. NaV1.6-M136V channels increase amplitude of transient and resurgent currents and increase neuronal firing. In this specific aim we will examine whether NaV1.6-M136V exacerbates VIP in a mouse model. Specific Aim 3: Assess the use of cannabinoids to ameliorate VIP. Cannabidiol (CBD) is FDA-approved for treatment of some forms of epilepsy and has been shown to block resurgent NaV1.6 currents at a concentration that spares peak transient current, and to reduce neuronal excitability. In this specific aim, we will determine whether treatment with CBD can ameliorate VIP. We will also compare the effect of CBD to FDA-approved duloxetine (Cymbalta®), which has sodium channel blocking activity and has been shown to be effective for treatment of CIPPN.