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.

项目摘要 现在有越来越多的证据表明，病理性疼痛状态依赖于 大脑本身的变化。已知下行调节通路介导顶部- 伤害性处理的下调，将皮质和边缘系统的影响传递到 脊髓的背角上升的疼痛传递途径也与 与这些调节系统交织在一起，形成正反馈和负反馈回路。 最具特征的疼痛调节系统的输出节点是吻侧 延髓腹内侧（RVM）。根据海因里希实验室的经验， RVM神经元的输出，本申请中的研究填补了一个重要的空白， 识别有害输入通过其到达RVM的途径。RVM有两个 疼痛调节细胞类型：“ON-细胞”，其对伤害感受产生净促进影响， 和具有净抑制作用的“OFF-细胞”。当前的首要目标 我们的建议是了解慢性疼痛状态下这种回路的可塑性，以及它是如何被激活的。 由内源性阿片类物质和大麻素调节。我们最近发现， 臂旁复合体（PB）是急性伤害性信息向RVM传递的重要中转站。我们 建议测试PB在调节RVM疼痛调节神经元的活性中的作用， 阐明阿片类物质和大麻素如何调节PB-RVM突触的活性， 确定这种连接在慢性疼痛状态下是如何改变的。这些研究将用于 来自鉴定的RVM ON-和OFF-细胞的体内单细胞记录，光遗传学，和 药理学操作，以检验PB投射到RVM的假设， 在持续炎症后进行调节（目标1）。作为对这种体内工作的补充， 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 通过光遗传学操作鉴定的PB-RVM末端来限定膜 PB-RVM突触的机制，并了解这些突触是如何调制的 大麻素和阿片类药物。我们还将确定这种连接是如何改变慢性 炎症通过定义有害信息到达疼痛的途径- 在膜、单个神经元和回路水平上调节神经元，我们可以开始 定义疼痛调节回路在急性和慢性疼痛中是如何被招募的。这些信息 如果我们要开发出治疗慢性疼痛的方法， 疾病