Varicella zoster virus-Induced Pain in a Rat Model of Post-Herpetic Neuralgia

 描述(由申请人提供)：带状疱疹后遗神经痛(PHN)是一种常见的、极度疼痛和虚弱的并发症，很难治疗，我无法满足对改进治疗的需求。当水痘-带状疱疹病毒(VZV)从水痘期间宿主感觉神经元建立的潜伏状态重新激活时，带状疱疹和PHN就会发生。全世界大多数成年人都有患带状疱疹、PHN和疼痛的风险，这些疾病可能会严重到严重降低生活质量的地步。发病率随着年龄的增长而增加，我们的老龄化社会意味着带状疱疹和PHN可能会成为更紧迫的公共卫生问题。VZV引起持续性疼痛的机制尚不清楚。本项目针对FOA PA-13-118，扩展了一种临床相关的PHN模型，在该模型中，VZV接种到大鼠足垫可诱导长时间的机械痛觉过敏和热痛敏。我们的假设是，这个模型将提供更好的理解VZV如何与神经系统相互作用来诱导疼痛，并成为测试改进的VZV诱导疼痛治疗方法的平台。目的1将确定VZV在大鼠体内表达和复制以诱导疼痛的要求。我们将测试这一假设，即在缺乏生产性复制的情况下，有限的VZV表达足以驱动慢性疼痛指标。我们还将测试假设，即VZV缺乏ORF47激酶，不会引起慢性疼痛，不能引发疼痛所需的大鼠感染。第三，我们将通过以下方式解决内部属性 其中VZV IE62转录调控因子诱导的慢性疼痛行为独立于其他VZV蛋白。这些研究将建立驱动模型中疼痛状态的VZV复制和表达的关键成分。目标2将重点放在感染神经元的作用上 对疼痛状态的贡献。我们将验证VZV蛋白表达的神经元直接驱动致痛行为的假设，开发一种创新的配体依赖的神经元特异性疼痛抑制系统，涉及甘氨酸受体的表达和配体的激活。我们还将讨论参与驱动疼痛状态的神经元亚型，这种疼痛状态是由复制缺陷单纯疱疹病毒(RdHSV)载体中神经元特异性启动子表达的特定VZV疼痛诱导蛋白诱导的。这也可以建立一个更长时间的VZV诱导的疼痛行为模型。目标3将介绍VZV引起的疼痛的改进和更具体的治疗。我们将测试表达配体依赖的甘氨酸受体的rdHSV在转录靶向特定神经元亚群后阻断VZV诱导的大鼠疼痛信号的有效性。这也将揭示那些传递VZV诱导的疼痛信号的神经元亚型。总而言之，这些方法有可能彻底改变我们思考VZV是如何引起疼痛的方式，以及我们如何更有效地为那些不幸的人类PHN患者提供缓解。

 DESCRIPTION (provided by applicant): Post-Herpetic Neuralgia (PHN) is a common, exceedingly painful and debilitating complication of Herpes Zoster that is difficult to treat and i unmet in the need for improved therapies. Zoster and PHN occur when varicella-zoster virus (VZV) reactivates from a latent state that was established in host sensory neurons during chickenpox. Most adults worldwide are at risk for Zoster, PHN and pain, which may be so severe as to profoundly reduce quality of life. Incidence increases with age, and our aging society implies Zoster and PHN may become even more pressing public health concerns. The mechanisms by which VZV causes persistent pain are not understood. This project, directed to FOA PA-13-118, expands a clinically relevant model of PHN in which VZV inoculated into the rat footpad induces prolonged mechanical allodynia and thermal hyperalgesia. Our overlying hypothesis is that this model will provide better comprehension of how VZV interacts with the nervous system to induce pain, and be a platform to test improved approaches for treatment of VZV-induced pain. Aim 1 will define the requirements of VZV expression and replication in the rat to induce pain. We will test the hypothesis that limited VZV expression is sufficient to drive chronic indicators of pain in the absence of productive replication. We will also test the hypothesis that VZV lacking the ORF47 kinase, which does not induce chronic pain, cannot initiate infection of the rat required for pain. Third, we will address the intrinsic properties by which the VZV IE62 transcriptional regulator induces chronic pain behaviors independent of other VZV proteins. These studies will establish the key components of VZV replication and expression in driving the pain state in the model. Aim 2 will focus on the role of infected neurons in contributing to the pain state. We will test the hypothesis that VZV protein expressing neurons directly drive nocifensive behaviors, exploiting an innovative ligand-dependent, neuron- specific pain repression system that involves expression of glycine receptors and activation by ligands. We will also address the neuron subtypes involved in driving a pain state that is induced by specific VZV pain-inducing proteins expressed from neuron-specific promoters in replication defective HSV (rdHSV) vectors. This could also establish a more prolonged model of VZV-induced pain behaviors. Aim 3 will address improved and more specific therapy of VZV-induced pain. We will test rdHSV expressing ligand-dependent glycine receptors for efficacy in blocking VZV induced pain signals in the rat following transcriptionally targeting of specific subpopulations of neurons. This will also reveal those neuron subtypes that transmit the VZV-induced pain signals. Together, these approaches have potential to revolutionize the way we think about how VZV induces pain and how we can more effectively provide relief to those unfortunate human patients suffering from PHN.