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疼痛状态取决于 大脑本身的变化。已知下降调节途径可以介导顶部 向下调节伤害性处理，将皮质和边缘的传播影响到对 脊髓的背角。上升的疼痛传播路径也很紧密 与这些调节系统交织在一起，形成正反馈循环。 最佳特征疼痛调节系统的输出节点是the the Rostral 腹侧髓质（RVM）。基于Heinricher实验室定义的经验 RVM神经元的输出，本应用中的研究填补了重要的空白， 识别有害输入到达RVM的途径。 RVM有两个 疼痛调节细胞类型：“网络”，净促进对伤害感受的净影响， 以及具有净抑制作用的“单元”。现在的总体目标 提案是了解慢性疼痛状态下该电路的可塑性，以及如何 由内源性阿片类药物和大麻素调节。我们最近表明 副型复合体（PB）是急性有害信息与RVM的关键继电器。我们 提议测试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，而 确定在慢性疼痛状态下如何改变这种联系。这些研究将用于 来自已识别的RVM的体内单细胞记录，On-On-和Off-Cell，Optogenogotogant和 测试PB投影RVM的药理操作是 调节持续注射后（目标1）。补充这项体内工作， AIM 2和3下的平行研究将在成年RVM切片中使用体外电生理学 通过对已识别的PB-RVM端子的光遗传操作以定义膜 PB-RVM突触的机制，并了解这些突触如何通过 大麻素和阿片类药物。我们还将确定在慢性中如何改变这种连接 炎。通过定义有害信息达到痛苦的途径 - 调节膜，单个神经元和电路水平的神经元，我们可以开始 定义如何在急性和慢性疼痛中募集疼痛调节电路。此信息 如果我们要开发针对慢性疼痛作为不良适应性大脑的治疗方法至关重要 疾病。