Lymphotoxin-beta receptor peripheral signaling regulates the transition to inflammation and neuropathy-induced chronic pain

慢性疼痛管理不善导致阿片类药物过量使用、与过量用药有关的死亡以及心血管、肾脏疾病 以及流行比例的神经系统并发症。要解决这些问题，有必要澄清 与控制启动和启动过程的基本机制有关的知识的严重差距 维持慢性疼痛状态。目前的研究范式表明，组织或神经损伤会触发 保护性免疫反应，应在其功能完成后立即解决。如果炎症不是 如果疼痛得到缓解，则可能发生从急性疼痛到慢性疼痛的过渡。我们建议，一个关键的监管机构 保护性免疫和免疫病理学之间的微妙平衡可能是很好的控制对象 组织或神经损伤后的持续炎症反应；随后，调节 慢性疼痛的发展。淋巴毒素-β受体(LT-βR)就是这种重要的调节因子之一。 肿瘤坏死因子受体家族的成员。这项提议的目的是澄清 以及外周LTβR信号如何调节疼痛的起始和维持过程 炎性和化疗诱导的周围神经病(CIPN)模型。基于现有的 文献和我们的初步数据，我们提出了一个全新的调控机制的发起和 维持炎症和CIPN疼痛，其中外周LTβR信号控制这些 通过调节转录和细胞可塑性网络在后爪和背根节细胞中的过程。 因此，我们的中心假设是外周LTβR信号控制启动过程 和维持炎症和CIPN疼痛通过控制转录和 细胞可塑性调节外周细胞和感觉神经元之间的通讯。我们的 假说将通过三个相互关联但又相互独立的目标来检验。目标1定义了 外周LT-β-R信号转导通路在炎性和环磷神经痛的启动和维持中的作用 雌性老鼠。目的2确定炎症和炎症过程中外周LTβR信号的细胞基础 CIPN疼痛。目的3研究外周LTβR信号对炎症和CIPN诱导的影响 PAW和DRG中感觉神经元和非神经元的转录和细胞可塑性。建议的研究是 创新是因为它描述了概念上新的外周调节机制，控制 慢性疼痛的启动和维持过程，由LTβR调节。 研究具有重要意义，因为它(1)促进了我们对调控从 急性到慢性疼痛；以及(2)提供LTβR信号拮抗剂作为预防的潜在治疗靶点 并完全和持续地逆转CIPN慢性疼痛，以及有效和持久地管理 炎症性疼痛。

Chronic pain mismanagement has led to opioid overuse, overdose related deaths and cardiovascular, renal and neurological complications at epidemic proportions. To combat these problems, it is essential to elucidate critical gaps in knowledge pertaining to the underlying mechanisms controlling the processes of initiation and maintenance of chronic pain conditions. The current paradigm implies that tissue or nerve damage triggers protective immune response that should be resolved as soon as its function is fulfilled. If inflammation is not resolved, then transition from the acute to chronic pain could occur. We propose that critical regulators of a delicate balance between protective immunity and immunopathology could be good candidates for controlling a sustained inflammatory response after tissue or nerve damage; and subsequently, regulating the process of development of chronic pain. One of such critical regulators is lymphotoxin-beta receptor (LTβR), a member of the tumor necrosis factor receptor family. The objective of this proposal is to elucidate whether and how peripheral LTβR signaling regulates the process of the initiation and maintenance of pain in inflammatory and chemotherapy-induced peripheral neuropathy (CIPN) models. Based on the existing literature and our preliminary data, we propose an entirely novel regulatory mechanism for the initiation and maintenance of inflammatory as well as CIPN pain wherein peripheral LTβR signaling controls these processes by regulating the network of transcriptional and cellular plasticity in hindpaw and DRG cells. Accordingly, our central hypothesis is that peripheral LTβR signaling controls the processes of initiation and maintenance of inflammatory and CIPN pain via governing the network of transcriptional and cellular plasticity mediating communication between peripheral cells and sensory neurons. Our hypothesis will be tested by three interconnected yet independent aims. Aim 1 defines the impact of peripheral LTβR signaling on the initiation and maintenance of inflammatory and CIPN pain in male and female mice. Aim 2 determines the cellular basis of LTβR signaling at the periphery during inflammatory and CIPN pain. Aim 3 examines the impact of peripheral LTβR signaling on inflammation- and CIPN-induced sensory neuronal and non-neuronal transcriptional and cell plasticity in paw and DRG. The proposed study is innovative because it describes conceptually novel peripheral regulatory mechanism controlling the processes of initiation and maintenance of chronic pain, which are regulated by LTβR. The proposed research is significant as it (1) advances our understanding of mechanisms regulating the transition from acute to chronic pain; and (2) offers LTβR signaling antagonists as potential therapeutic targets for prevention and full and sustained reversal of CIPN chronic pain, as well as effective and long-lasting management of inflammatory pain.