Novel Circuits and Mechanisms of Descending Pain Modulation

下行疼痛调节的新颖电路和机制

• 批准号: 10608691
• 负责人: ALEXANDER G BASSUK
• 金额: $ 55.06万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608691
• 关键词: Acute Pain; Address; Affect; Analgesics; Attenuated; Axon; Behavior; C Fiber; Capsaicin; Cells; Characteristics; Clozapine; Complex; Data; Designer Drugs; Development; Genetic; Glutamate Decarboxylase; Hypersensitivity; Image; Inflammation; Inflammatory; Injections; Knowledge; Label; Lateral; Mechanics; Mediating; Modeling; Neurobiology; Neurons; Neuropathy; Nociception; Output; Oxides; Pain; Pain management; Pathway interactions; Patients; Persistent pain; Phase; Play; Pontine structure; Pre-Clinical Model; Preparation; Regulation; Role; Signal Transduction; Spinal; Spinal Cord; Spinal cord posterior horn; Synapses; Synaptic Transmission; Testing; Tyrosine 3-Monooxygenase; Vertebral column; Work; antinociception; behavior test; chronic pain; dorsal horn; genetic approach; genetic manipulation; inflammatory pain; innovation; interdisciplinary approach; midbrain central gray substance; mouse model; multi-photon; nerve injury; neural circuit; noradrenergic; novel; optogenetics; pain processing; painful neuropathy; parabrachial nucleus; patch clamp; presynaptic; prodynorphin; spared nerve; targeted treatment; two-photon

Project Summary/Abstract Chronic pain afflicts millions of patients, yet treatments are largely ineffective, and development of new, targeted therapies is limited by knowledge gaps in the neurobiology of pain. Despite recent progress, key questions remain about the incredibly complex cellular and functional organization of ascending and descending neural circuits that control pain processing. Answering these questions is essential for developing new, more efficacious, and better targeted therapeutics for acute and chronic pain. The main objective of this proposal is to identify the circuit connections and synaptic mechanisms of a novel group of neurons that we recently discovered in the lateral pons. Situated juxta the A5 noradrenergic cell group, these neurons (which we termed LJA5) express prodynorphin and glutamic acid decarboxylase 1 (GAD1). They are distinct from the A5 noradrenergic neurons as they do not express tyrosine hydroxylase. LJA5 neurons project to all spinal levels of lamina I of the dorsal horn (DH), as well as to the parabrachial nucleus (PB) and the periaqueductal gray (PAG). Notably, we showed that these neurons play an important role in pain regulation. Specifically, chemogenetic activation of LJA5 neurons suppressed capsaicin- and inflammation-induced mechanical pain, but not thermal sensitivity, whereas chemogenetic inhibition of LJA5 enhanced mechanical hypersensitivity during inflammation. Our preliminary data also showed that chemogenetic activation of LJA5 neurons strongly attenuated neuropathic pain both via systemic and intrathecal administration of a designer drug. Collectively, these findings suggest that LJA5 neurons and their projections represent a novel component of descending pain modulation, and also pose many important questions about this novel circuit: 1) Which types of pain are regulated by LJA5 neurons? 2) What are the key projections/outputs of LJA5 neurons? 3) What synaptic mechanisms are utilized by LJA5 neurons? Our central hypothesis is that LJA5 neurons modulate pain processing by controlling synaptic transmission in lamina I of the dorsal horn of the spinal cord. We will test this hypothesis in 3 specific aims by using a multidisciplinary approach that includes chemogenetic manipulation combined with behavioral testing, patch-clamp recording in innovative intact spinal cord preparation and 2-photon Ca2+ imaging in axonal boutons of primary afferent central terminals. Aim 1 will establish the role of LJA5 neurons in mouse models of inflammatory and neuropathic pain. Aim 2 will examine functional significance of the main LJA5 projections. Aim 3 will determine synaptic mechanisms that mediate the antinociceptive effects of LJA5 neurons in the spinal cord. This proposal will define fundamental characteristics of a novel descending pathway involved in pain modulation, including its functional connectivity, synaptic mechanisms and its role in acute and chronic pain states. This work is transformative because it identifies a novel bulbospinal pain modulatory pathway, a significant advance in our basic understanding of pain that may offer alternative approaches to pain control.

项目概要/摘要 慢性疼痛困扰着数百万患者，但治疗方法基本上无效，需要开发新的、有针对性的药物 治疗方法受到疼痛神经生物学知识空白的限制。尽管最近取得了进展，但关键问题 仍然是关于上行和下行神经的极其复杂的细胞和功能组织 控制疼痛处理的电路。回答这些问题对于开发新的、更多的内容至关重要 针对急性和慢性疼痛的有效且更有针对性的治疗方法。该提案的主要目标是 识别我们最近发现的一组新神经元的电路连接和突触机制 在脑桥外侧。这些神经元（我们称之为 LJA5）位于 A5 去甲肾上腺素能细胞群旁边 表达强啡肽原和谷氨酸脱羧酶 1 (GAD1)。它们与 A5 去甲肾上腺素能不同 神经元，因为它们不表达酪氨酸羟化酶。 LJA5 神经元投射到 I 层的所有脊髓水平 背角（DH），以及臂旁核（PB）和导水管周围灰质（PAG）。值得注意的是，我们 表明这些神经元在疼痛调节中发挥重要作用。具体而言，化学遗传学激活 LJA5 神经元抑制辣椒素和炎症引起的机械性疼痛，但不能抑制热敏感性， 而 LJA5 的化学遗传学抑制则增强了炎症过程中的机械超敏反应。我们的 初步数据还表明，LJA5 神经元的化学遗传学激活可强烈减弱神经病变 通过全身和鞘内施用设计药物来缓解疼痛。总的来说，这些发现表明 LJA5 神经元及其投射代表了下行疼痛调节的新组成部分，并且也构成了 关于这个新颖的回路有许多重要的问题：1）哪些类型的疼痛是由 LJA5 神经元调节的？ 2） LJA5 神经元的关键投射/输出是什么？ 3) LJA5利用了哪些突触机制 神经元？我们的中心假设是 LJA5 神经元通过控制突触来调节疼痛处理 脊髓背角第一层的传输。我们将在 3 个具体目标中检验这一假设： 使用多学科方法，包括化学遗传学操作与行为测试相结合， 创新完整脊髓制备中的膜片钳记录和轴突扣中的 2 光子 Ca2+ 成像 初级传入中枢终端。目标 1 将建立 LJA5 神经元在小鼠模型中的作用 炎症性疼痛和神经性疼痛。目标 2 将检查主要 LJA5 预测的功能意义。目的 3将确定介导脊髓中LJA5神经元的抗伤害作用的突触机制 绳索。该提案将定义涉及疼痛的新型下行通路的基本特征 调节，包括其功能连接、突触机制及其在急性和慢性疼痛中的作用 州。这项工作具有变革性，因为它确定了一种新的球脊髓疼痛调节途径，即 我们对疼痛的基本理解取得了重大进展，可能为疼痛控制提供替代方法。