Cannabinoid and opioid modulation of descending pain circuits in chronic pain

大麻素和阿片类药物对慢性疼痛中下行疼痛回路的调节

• 批准号: 9904615
• 负责人: Mary Magdalen Heinricher
• 金额: $ 40.17万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904615
• 关键词: Acute; Acute Pain; Address; Adult; Animal Model; Behavior; Brain; Brain Diseases; Brain Stem; Cannabinoids; Cells; Chronic; Chronic inflammatory pain; Complement; Complex; Data; Down-Regulation; Electrophysiology (science); Endocannabinoids; Feedback; Goals; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Label; Laboratories; Link; Mediating; Membrane; Methods; Modeling; Molecular; Neuraxis; Neurons; Neurotransmitters; Nociception; Opioid; Output; Pain; Pathologic; Pathway interactions; Patients; Persistent pain; Pharmacology; Physiological; Rodent; Role; Signal Transduction; Slice; Spinal cord posterior horn; Synapses; Syndrome; System; Testing; Work; active control; cell type; chronic pain; dorsal horn; endogenous opioids; in vivo; insight; laboratory experience; mu opioid receptors; neurotransmitter release; novel; optogenetics; pain behavior; recruit; transmission process

PROJECT SUMMARY There is now increasing evidence that pathological pain states are dependent on changes in the brain itself. Descending modulatory pathways are known to mediate top- down regulation of nociceptive processing, transmitting cortical and limbic influences to the dorsal horn of the spinal cord. Ascending pain transmission pathways are also intimately intertwined with these modulatory systems, forming positive and negative feedback loops. The output node of the best-characterized pain-modulating system is the rostral ventromedial medulla (RVM). Building on the Heinricher laboratory's experience defining the outputs of RVM neurons, the studies in the present application fill an important gap, identifying a pathway through which noxious input reaches the RVM. The RVM has two pain-modulating cell types: “ON-cells,” which exert a net facilitating influence on nociception, and “OFF-cells,” which have a net inhibitory action. The overarching goals of the present proposal are to understand plasticity of this circuitry in chronic pain states, and how it is modulated by endogenous opioids and cannabinoids. We recently showed that the parabrachial complex (PB) is a critical relay of acute noxious information to the RVM. We propose to test the role of the PB in regulating the activity of RVM pain-modulating neurons, elucidate how opioids and cannabinoids modulate the activity of PB-RVM synapses, and determine how this connection is altered in chronic pain states. These studies will use in vivo single-cell recording from identified RVM ON- and OFF-cells, optogenetics, and pharmacological manipulations to test the hypothesis that the PB projection to the RVM is modulated following persistent inflammation (Aim 1). Complementing this in vivo work, parallel studies under Aims 2 and 3 will use in vitro electrophysiology in an adult RVM slice with optogenetic manipulation of identified PB-RVM terminals to define the membrane mechanisms of PB-RVM synapses and understand how these synapses are modulated by cannabinoids and opioids. We will also determine how this connection is altered in chronic inflammation. By defining pathways through which noxious information reaches pain- modulating neurons at the membrane, individual neuron, and circuit level, we can begin to define how pain-modulating circuits are recruited in acute and chronic pain. This information is critical if we are ever to develop treatments addressing chronic pain as maladaptive brain disease.

项目概要 现在越来越多的证据表明病理性疼痛状态取决于 大脑本身的变化。已知下行调节途径介导顶部- 下调伤害感受处理，将皮质和边缘系统的影响传递给 脊髓的背角。上行疼痛传递途径也密切相关 与这些调节系统交织在一起，形成正反馈回路和负反馈回路。 最具特征的疼痛调节系统的输出节点是吻端 腹内侧延髓（RVM）。以 Heinricher 实验室的经验为基础，定义 RVM神经元的输出，本申请的研究填补了一个重要的空白， 识别有害输入到达 RVM 的途径。 RVM 有两个 疼痛调节细胞类型：“ON-细胞”，对伤害感受产生净促进影响， 和“OFF-cells”，具有净抑制作用。当前的总体目标 建议了解慢性疼痛状态下该回路的可塑性，以及它是如何发生的 受内源性阿片类药物和大麻素调节。我们最近表明 臂旁复合体 (PB) 是急性有害信息到 RVM 的关键中继。我们 建议测试 PB 在调节 RVM 疼痛调节神经元活性中的作用， 阐明阿片类药物和大麻素如何调节 PB-RVM 突触的活性，以及 确定这种联系在慢性疼痛状态下如何改变。这些研究将用于 来自已识别的 RVM ON 和 OFF 细胞的体内单细胞记录、光遗传学和 药理操作来检验 PB 投影到 RVM 的假设 持续炎症后进行调节（目标 1）。作为体内工作的补充， 目标 2 和 3 下的平行研究将在成人 RVM 切片中使用体外电生理学 通过对已识别的 PB-RVM 末端进行光遗传学操作来定义膜 PB-RVM 突触的机制并了解这些突触是如何被调节的 大麻素和阿片类药物。我们还将确定这种联系在慢性病中如何改变 炎。通过定义有害信息到达痛苦的途径 在膜、单个神经元和电路水平上调节神经元，我们可以开始 定义如何在急性和慢性疼痛中招募疼痛调节回路。此信息 如果我们要开发出解决大脑适应不良引起的慢性疼痛的治疗方法，这一点至关重要 疾病。