Dorsal horn circuits for mechanical allodynia

用于机械异常性疼痛的背角电路

• 批准号: 9977288
• 负责人: REBECCA P SEAL
• 金额: $ 51.61万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977288
• 关键词: Acute; Afferent Neurons; Anatomy; Applications Grants; Behavior; Behavioral; Cells; Cholecystokinin; Clinical; Development; Disinhibition; Electrophysiology (science); FOS gene; Fiber; Genetic; Goals; High Prevalence; In Vitro; Inflammatory; Injury; Interneurons; Intrathecal Injections; Mechanics; Mediating; Modeling; Molecular; Monitor; Movement; Nature; Nerve Tissue; Neurons; Neuropathy; Nociception; Pain; Persistent pain; Population; Posterior Horn Cells; Process; Rabies virus; Role; Slice; Spinal Cord; Synapses; Techniques; Testing; Therapeutic Intervention; Touch sensation; Up-Regulation; Work; behavior test; calretinin; design; dorsal horn; effective therapy; experimental study; in vitro Model; in vivo; inflammatory neuropathic pain; integration site; mechanical allodynia; neural circuit; neuromechanism; novel; novel therapeutic intervention; pain model; postsynaptic; protein kinase C gamma; receptor; somatosensory; tool; transmission process

Pain continues to be a major clinical problem due to its high prevalence and lack of adequate treatment options. The identification of more effective therapies is hampered by a lack of understanding of the neural circuits and mechanisms that underlie pain. Work outlined in this proposal is focused on delineating the dorsal horn circuits for mechanical allodynia, a common condition in which touch or movement become painful after injury. The dorsal horn is a major site for the integration of somatosensory information. It is also where injury- induced changes in the circuitry give rise to mechanical allodynia. In studies to elucidate the dorsal horn mechanical allodynia circuits, we have identified populations of dorsal horn excitatory interneurons that mediate this form of pain. Additionally, we present evidence supporting the concept that the neural circuitry that mediates mechanical allodynia in the dorsal horn differs depending on the nature of the injury. Thus, the overarching goal of this project is to delineate the dorsal horn circuits underlying mechanical allodynia in the context of the type of injury, inflammatory and neuropathic. In Aim 1) we will determine whether the populations of excitatory interneurons are required for mechanical allodynia produced by models of inflammatory and neuropathic pain. In Aim 2) we will expand our understanding of the dorsal horn circuitry related to these excitatory interneuron populations under naïve conditions by identifying the neurons monosynaptically connected to them. This more detailed picture of the basic dorsal horn circuitry will facilitate experiments aimed at identifying key changes that underlie mechanical allodynia caused by different types of injuries. In Aim 3) we will use an in vitro model of mechanical allodynia to test the role of these excitatory interneuron populations in inflammatory and neuropathic pain models. This will allow us to assess on a synaptic level the role of these neurons in mechanical allodynia in the context of injury-type. Classes of afferents and populations of lamina I projection neurons will also be assessed. These novel studies will provide a critical anatomical framework with which to advance molecular- and synaptic-level studies of the neurons and mechanisms that underlie mechanical allodynia as well as generate new therapeutic strategies.

由于其高患病率和缺乏适当的治疗，疼痛仍然是一个主要的临床问题 选项.由于缺乏对神经系统的了解， 疼痛的神经回路和机制本提案中概述的工作重点是描绘背侧 用于机械性异常性疼痛的喇叭电路，一种常见的情况，其中触摸或运动在 损伤背角是躯体感觉信息整合的主要部位。这也是受伤的地方-- 电路中的诱发变化引起机械异常性疼痛。在阐明背角的研究中 机械异常性疼痛回路，我们已经确定了背角兴奋性中间神经元的群体， 缓解这种疼痛。此外，我们提出的证据支持的概念，神经电路， 介导背角中的机械性异常性疼痛取决于损伤的性质而不同。因此 这个项目的首要目标是描绘背角回路潜在的机械异常性疼痛， 损伤类型的背景，炎性和神经性。在目标1）中，我们将确定 兴奋性中间神经元的群体是由模型产生的机械异常性疼痛所需要的。 炎性和神经性疼痛。在目标2）中，我们将扩展对背角回路的理解 与这些兴奋性中间神经元群体在天真的条件下，通过识别神经元 单突触连接到它们。这张更详细的背角基本电路图将有助于 旨在确定由不同类型的机械性异常性疼痛引起的关键变化的实验， 受伤在目的3）中，我们将使用机械性异常性疼痛的体外模型来测试这些兴奋性神经元的作用。 炎症和神经性疼痛模型中的中间神经元群体。这将使我们能够评估一个 突触水平的作用，这些神经元在机械异常性疼痛的背景下，损伤型。类 还将评估板层I投射神经元的传入和群体。这些新的研究将提供 一个关键的解剖框架，用于推进神经元的分子和突触水平研究， 机械性异常性疼痛的潜在机制以及产生新的治疗策略。