Glucocorticoids and endocannabinoids in vagal complex

迷走神经复合体中的糖皮质激素和内源性大麻素

• 批准号: 7999255
• 负责人: Bret N Smith
• 金额: $ 31.23万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999255
• 关键词: Accounting; Affect; Agonist; Anxiety; Applications Grants; Area; Binding; Biochemical; Blood; Brain; Brain Stem; Calcium; Cannabinoids; Cell membrane; Cells; Characteristics; Complex; Data; Dependence; Digestion; Disease; Endocannabinoids; Enzymes; Ethanolamines; G-Protein-Coupled Receptors; Glucocorticoids; Glucose; Glutamates; Health; Hormones; Hypertension; Hypothalamic structure; Knowledge; Ligand Binding; Ligands; Lipase; Mediating; Membrane; Metabolic; Methods; Moods; Movement; Multiple Sclerosis; Nervous system structure; Neurons; Obesity; Output; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phosphotransferases; Presynaptic Terminals; Rattus; Receptor Activation; Reflex action; Regulation; Research Project Grants; Slice; Stimulus; Synapses; System; Testing; Therapeutic Uses; Time; Transgenic Mice; Vanilloid; Viscera; Visceral; anandamide; base; body system; chemical release; dorsal motor nucleus; endogenous cannabinoid system; feeding; gamma-Aminobutyric Acid; insulin secretion; neurotransmission; neurotransmitter release; painful neuropathy; patch clamp; postsynaptic; receptor; research study; response

DESCRIPTION (provided by applicant): The experiments in this research grant proposal will identify the cellular and synaptic effects of endogenous cannabinoid (eCB) ligands and of glucocorticoid-induced release of eCBs in the dorsal motor nucleus of the vagus (DMV). Neurons in the DMV regulate parasympathetic output to most of the subdiaphragmatic viscera and therefore critically control feeding, digestion, glucose and insulin secretion, and other metabolic functions. Their activity is largely controlled by synaptic input to the DMV, which is modulated by locally released chemicals and circulating hormones. Regulation of DMV neurons by cannabinoids, vanilloids, and glucocorticoids has been suggested; when applied centrally these compounds profoundly alter parasympathetic function. Several eCB ligands, which are thought to be released from cell membranes in a retrograde fashion, activate both cannabinoid type 1 receptors (CB1R) and transient receptor potential vanilloid type 1 (TRPV1). In the DMV, activation of TRPV1 enhances neurotransmitter release, whereas CB1R tends to inhibit synapses. Both effects occur by activation of receptors on presynaptic terminals. Preliminary evidence suggests that eCB ligands are released from DMV neurons, and that glucocorticoids or depolarization can induce this release. Thus, eCB activity in the DMV may modulate both TRPV1 and CB1R activity. Neither the type(s) of eCB ligands released, the effects of most eCB ligands on synaptic activity, nor the trigger or mechanism of eCB release in the DMV are known. We will use whole-cell patch-clamp recordings from DMV neurons in brainstem slices to identify effects of eCB ligands on cellular activity in the DMV, and will also identify the compounds released by cells in the area using pharmacological and biochemical methods. The experiments will be guided by three specific aims: 1) Differentiate effects of eCB ligands on CB1R and TRPV1 in the DMV; 2) Determine the eCB involvement in mediating rapid effects of glucocorticoids on local circuitry in the DMV; and 3) Identify the cellular pathway of the glucocorticoid effect. We will test the hypotheses that eCBs alter TRPV1 and CBR1 activity in the DMV in specific and predictable spatial, temporal, functionally relevant, and activity-dependent patterns, and that glucocorticoids induce eCB release from DMV cells by acting at membrane-bound G protein-coupled receptors on DMV neurons. Drugs based on the eCB system are being investigated for therapeutic use in a variety of nervous system pathologies, including disorders related to feeding, digestion, and obesity. Glucocorticoids, which release eCBs in some systems, are widely prescribed, and are also released by stressful stimuli. Results of these studies will be critical to predicting and understanding how these compounds interact with each other and affect parasympathetic function. Possible translational benefits also exist because of the benefit in controlling eCB levels in the vagal system of patients with elevated glucocorticoids. PUBLIC HEALTH RELEVANCE Endogenous cannabinoid compounds have particularly complex actions in the area of the brainstem most responsible for maintaining functions of organ systems, and a number of drugs therapies based on altering these compounds in the brain are being developed without knowledge about their effects in this critical brain area. The experiments in this research grant proposal will identify the characteristics of these drugs, how they are released by glucocorticoid hormones, and what actions they have on the neurons. Results of these studies will be critical for predicting and understanding how these compounds interact to affect digestive functions, and they will also be applicable to multiple other neuronal systems.

描述（由申请人提供）：本研究赠款提案中的实验将确定内源性大麻素（ECB）配体的细胞和突触作用以及糖皮质激素引起的ECB在Vagus的背运动核中的释放（DMV）。 DMV中的神经元调节副交感神经输出对大多数次脑副内脏，因此严格控制进食，消化，葡萄糖和胰岛素分泌以及其他代谢功能。它们的活性在很大程度上通过DMV的突触输入来控制，DMV受到局部释放的化学物质和循环激素的调节。已经提出了大麻素，香草素和糖皮质激素对DMV神经元的调节。当中央应用时，这些化合物会深刻改变副交感神经功能。据认为以逆行方式从细胞膜释放的几种欧洲央行配体激活了大麻素1型受体（CB1R）和瞬态受体势能1型1型（TRPV1）。在DMV中，TRPV1的激活增强了神经递质的释放，而CB1R倾向于抑制突触。两种影响都通过激活受体对突触前末端的激活而发生。初步证据表明，欧洲央行配体是从DMV神经元释放的，糖皮质激素或去极化可以诱导此释放。因此，DMV中的ECB活性可能会调节TRPV1和CB1R活性。已知欧洲央行配体的类型，大多数欧洲央行配体对突触活动的影响，以及DMV中欧洲央行释放的触发器或机制。我们将使用来自脑干切片中DMV神经元的全细胞斑块钳记录来识别欧洲央行配体对DMV中细胞活性的影响，并还将使用药理和生化方法鉴定细胞在该地区释放的化合物。实验将由三个特定目的指导：1）区分欧洲央行配体对DMV中CB1R和TRPV1的影响； 2）确定欧洲央行参与介导糖皮质激素对DMV局部电路的快速影响； 3）确定糖皮质激素作用的细胞途径。我们将测试在DMV中ECB在特定且可预测的空间，时间，功能相关和活性依赖性模式中改变DMV中TRPV1和CBR1活性的假设，并且通过作用于膜结合的G蛋白与DMV神经元上的膜结合G蛋白结合的受体在DMV细胞中释放糖皮质激素。正在研究基于欧洲央行系统的药物，以在多种神经系统病理中进行治疗，包括与喂养，消化和肥胖有关的疾病。在某些系统中释放ECB的糖皮质激素已被广泛规定，并且也通过压力刺激释放。这些研究的结果对于预测和理解这些化合物如何相互相互作用并影响副交感神经功能至关重要。由于糖皮质激素升高的患者的迷走神经系统控制欧洲央行水平的好处，也可能存在转化益处。公共卫生相关性内源性大麻素化合物在最负责维持器官系统功能的脑干区域中具有特别复杂的作用，并且基于改变大脑中这些化合物的许多药物疗法正在开发中，而在这个关键的大脑区域中没有任何知识。本研究赠款建议中的实验将确定这些药物的特征，糖皮质激素如何释放出来以及它们对神经元的作用。这些研究的结果对于预测和了解这些化合物如何相互作用以影响消化功能至关重要，并且它们也适用于多个其他神经元系统。