Defining the descending pain modulatory circuit

定义下行疼痛调节回路

• 批准号: 10461117
• 负责人: Mary Magdalen Heinricher
• 金额: $ 4.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2022-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461117
• 关键词: Absence of pain sensation; Acute Pain; Adult; Area; Automobile Driving; Behavior; Behavioral; Brain; Brain Stem; Cells; Complement; Complex; Development; Electrophysiology (science); Equilibrium; Freund' s Adjuvant; Goals; Heterogeneity; Hyperalgesia; In Vitro; Inflammation; Inflammatory; Injections; Label; Laboratories; Link; Maps; Maternal Behavior; Measures; Mediating; Molecular; Neuraxis; Neurons; Nociception; Opioid; Opioid Analgesics; Output; Pain; Pain management; Pathway interactions; Peripheral; Persistent pain; Pharmacology; Physiological; Population; Property; Rattus; Reproduction; Role; Sensory; Slice; Spinal cord posterior horn; Stress; Synapses; Synaptic plasticity; System; Testing; Viral; Work; cell type; chronic pain; dorsal horn; experimental study; in vivo; insight; midbrain central gray substance; mu opioid receptors; neurotransmitter release; optogenetics; pain behavior; pain inhibition; recruit; response; transmission process

PROJECT SUMMARY The central nervous system has an intrinsic pain modulatory system that regulates nociceptive processing through descending projections from the brainstem to the spinal cord dorsal horn. The ventrolateral periaqueductal gray (vlPAG) integrates sensory information with input from higher cortical and subcortical areas, and sends projections to the rostral ventromedial medulla (RVM) that are relayed to the dorsal horn of the spinal cord. Both the vlPAG and RVM are heterogenous with respect to participating in multiple behavioral circuits. The proposed studies build on extensive previous work from the Heinricher laboratory that has defined the output from the RVM, showing that bidirectional pain control from this region is mediated by two physiologically defined cell classes, “ON-cells” and “OFF-cells,” that respectively facilitate and inhibit dorsal horn nociceptive transmission under different conditions. The Ingram laboratory has expertise studying opioid actions within the PAG and RVM, as well as adaptations in both areas with persistent inflammation. Proposed viral optogenetic strategies will map and define the vlPAG circuit that regulates RVM ON-cells involved in the facilitation of pain and elucidate underlying cellular mechanisms that shift the balance of RVM output from inhibition of pain to facilitation of pain with persistent inflammation. The combined expertise of the two laboratories will focus on identified PAG-RVM synapses using optogenetic stimulation of RVM terminals originating from the PAG. In vitro brain-slice recordings (Ingram lab) will examine the heterogeneity of PAG output to the RVM and PAG-RVM synapses, as well as cellular mechanisms of synaptic plasticity induced in persistent inflammation. These studies will use a fluorescent label for the μ-opioid receptor to differentiate presumed ON-cells from other classes in the slice to determine whether PAG terminals directly synapse on ON-cells, OFF-cells, or both, as well as what neurotransmitters are released. In vivo single-cell recording studies (Heinricher lab) will determine how inflammation-induced changes in PAG-RVM synapses control excitability of specific populations of RVM neurons and establish the link between these changes and pain behaviors. A better understanding of molecular, cellular, and circuit-level mechanisms that underlie pain is essential if we are to develop better treatments. By carefully mapping the descending projections from PAG to RVM during the development of persistent inflammation, and by tying these to defined RVM outputs and behavior, we can begin to determine the interactions in this complex network, and gain new insights into how pain-modulating systems are recruited and modulated in acute and chronic pain.

项目摘要 中枢神经系统具有固有的疼痛调节系统，可调节伤害感受处理 通过从脑干到脊髓背角的下降项目。腹外侧 灰灰色（VLPAG）与高层皮质和皮层下的输入集成了感觉信息 区域，并将项目发送到传递到背喇叭的Rostral腹侧髓质（RVM） 脊髓。 VLPAG和RVM相对于参与多种行为而言都是异质的 界。拟议的研究以定义的Heinricher实验室的大量先前工作为基础 RVM的输出，表明该区域的双向疼痛控制是由两个介导的 物理定义的细胞类别，即“单细胞”和“非单元”，分别有助于和抑制背侧 喇叭在不同条件下的伤害性传播。 Ingram实验室有专家研究 PAG和RVM内的行动，以及持续发炎的两个地区的适应。建议的 病毒遗传策略将映射和定义VLPAG电路，该电路调节涉及的RVM 促进疼痛和阐明基本的细胞机制，使RVM输出的平衡从 抑制疼痛以持续炎症支持疼痛。两者中的联合专家 实验室将使用RVM端子的光遗传学模拟来关注已识别的PAG-RVM突触 起源于PAG。体外脑部滑板记录（INGRAM LAB）将检查PAG的异质性 输出RVM和PAG-RVM突触，以及引起的突触可塑性的细胞机制 持续的炎症。这些研究将使用荧光标签作为μ阿片受体来区分 假定从切片中其他类别的其他类别的元素来确定PAG终端是否直接突触 释放的电池，外元或两者以及神经递质的释放。体内单细胞记录 研究（Heinricher Lab）将确定炎症诱导的PAG-RVM突触控制的变化如何 RVM神经元特定种群的兴奋性，并在这些变化与疼痛之间建立联系 行为。更好地理解疼痛构成的分子，细胞和电路级机制是 如果要开发更好的治疗方法，至关重要。通过仔细映射从pag的下降项目到 RVM在持续感染的发展过程中，并将其与定义的RVM输出和 行为，我们可以开始确定这个复杂网络中的交互，并获得有关如何 招募和调节疼痛调节系统以急性和慢性疼痛调节。