Central Kappa Opioid Neural Regulation of Cardiovascular and Renal Function

中枢卡帕阿片类药物对心血管和肾功能的神经调节

基本信息

批准号：
7762534
负责人：
HELMUT B GOTTLIEB
金额：
$ 11.2万
依托单位：
UNIVERSITY OF THE INCARNATE WORD
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-08 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7762534
关键词：
Address Affinity Agonist Animal Experimentation Animal Model Animals Applications Grants Aptitude Area Ascites Award Bilateral Blood Circulation Body Fluids Brain region Cardiovascular Physiology Cardiovascular system Cells Cessation of life Chemistry Chronic Chronic Disease Cirrhosis Clinical Collaborations Congestive Heart Failure Conscious Data Development Disease Diuresis Diuretics Drug Receptors Dynorphin A Economic Burden Electrolyte Disorder Electrolytes Electrophysiology (science)Equilibrium Ethics Excitatory Neurotoxins Excretory function Experimental Models Extramural Activities Faculty Fellowship Fluid overload Funding Future G-Protein-Coupled Receptors Goals Grant Health Sciences Healthcare Systems Histocytochemistry Homeostasis Hormonal Hormones Hyponatremia Hypothalamic structure In Situ Hybridization Injection of therapeutic agent Investigation Journals Kidney Knowledge Lead Left Lesion Liquid substance Liver Cirrhosis Lung Manuscripts Measures Mediating Medical Economics Mentors Methods Modality Modification Molecular Biology Molecular Biology Techniques Molecular Structure Nerve Neural Pathways Neuraxis Neuroanatomy Neurons Operative Surgical Procedures Opioid Opioid Receptor Outcome Outcome Study Pathologic Pathology Pathway interactions Patients Peptides Peripheral Pharmaceutical Chemistry Pharmacology Physiological Physiology Plants Plasma Play Portal Hypertension Positioning Attribute Postdoctoral Fellow Prevention Proteins Publications Quality of life RNA Rattus Receptor Activation Recruitment Activity Regulation Relative (related person)Renal function Research Right kidney Rodent Role Saline Salvia Site Sodium Solid Son Staging Staining method Stains System Techniques Testing Texas Therapeutic Therapeutic Agents Therapeutic Uses Universities Urine Vasopressins Water Western Blotting Work abstracting acute stress amino group base career cost experience graduate student hemodynamics in vivo innovation interest kappa opioid receptors magnocellular mind control neuroregulation novel novel therapeutics paraventricular nucleus parvocellular post-doctoral training prevent professor public health relevance research study response salvinorin A skills

项目摘要

DESCRIPTION (provided by applicant): In certain pathophysiological states (e.g., cirrhoses with ascites), changes in the integrity of arterial circulation can lead to profound changes in renal excretion of fluid and electrolytes via the activation of neuronal and humoral mechanisms in the CNS and periphery. Chronic activation of these systems can produce hyponatremia, pulmonary congestion, and eventual death. The activation of central kappa opioids produce a marked water diuresis (an increase in urine flow without a concurrent increase in renal sodium excretion), which is different than traditional diuretics clinically used to date (which, enhance water and sodium excretion). Purpose: The goal of these studies is to identify the CNS sites and neuropathways by which central kappa opioid systems modulate renal function in normal and cirrhotic rats. Research Question: What are the central nervous system mechanisms and pathways responsible for the kappa opioid mediated renal effects? The following Specific Aims will be addressed: 1) determine the CNS regions involved in the diuretic, antinatriuretic and RSNA produced by the activation of central kappa opioid systems. Methods: RNA in situ hybridization histochemistry in conjunction with cFos or ICER studies will determine which CNS sites are being directly modulated by kappa opioid agonists (ICV) in normal and cirrhotic rats. Western Blot analysis will determine the kappa opioid receptor and peptide protein levels in these regions. Retrograde tract tracing will be used to identify regions that may influence the activity of parvocellular PVN and also express cFos and/or ICER 2) establish the role of the PVN parvocellular neurons and relevant CNS sites on cardiovascular and renal function produced by central activation of kappa opioids. Methods: Excitotoxin lesions studies will be performed to determine the role of the PVN and other CNS sites identified in Specific Aim 1 in the kappa- mediated effects on urine flow, renal sodium excretion and RSNA. In separate experiments, plasma vasopressin will be measured in rats with bilateral lesions of the PVN. Outcomes: This study will provide basic knowledge on how different systems interact and modulate water and sodium balance under normal and pathologic conditions, which is crucial for the prevention and treatment of diseases. Ultimately, opioid compounds can be developed and used to treat fluid overload/hyponatremia in susceptible patients and improvement of one's quality of life. PUBLIC HEALTH RELEVANCE: This grant proposal will provide new and important information regarding opioids and the central neurohumoral regulation of renal function and will ultimately provide a new strategy for therapeutic modalities for different cardiovascular and renal pathologies. It is possible that knowledge obtained from these investigations may lead to the development of new pharmacological therapeutic agents for the treatment of fluid and electrolyte disorders.

描述（由申请人提供）：在某些病理生理状态（例如，带有腹水的Cirrhose），动脉循环的完整性的变化可以通过激活CN和外围的神经元和体液机制，从而导致液体和电解质的肾脏排泄的深刻变化。这些系统的慢性激活会导致低钠血症，肺部充血和最终死亡。中央卡帕阿片类药物的激活产生明显的水利尿剂（尿液流量增加而没有同时增加肾脏排泄物的增加），这与临床上使用的传统利尿剂（增强水和钠排泄物）不同。目的：这些研究的目的是确定中央喀巴阿片类系统在正常和肝硬化大鼠中调节肾功能的中枢神经系统部位和神经病道。研究问题：中枢神经系统机制和途径是造成卡帕阿片类药物介导的肾作用的？将解决以下具体目的：1）确定与中央喀巴阿片类药物系统激活产生的利尿剂，抗钠和rSNA有关的中枢神经系统区域。方法：与CFO或ICER研究结合使用的RNA原位杂交组织化学将确定哪些CNS位点在正常和ciRRHotic大鼠中由Kappa阿片类动力学家（ICV）直接调节。蛋白质印迹分析将确定这些区域中的Kappa阿片受体和肽蛋白水平。逆行路面追踪将用于识别可能影响细胞细胞PVN活性的区域，并表达CFO和/或ICER 2）确定PVN副细胞神经元和相关CNS位点在心血管和肾功能上由Kappa阿片类阿片类阿片类阿片类药物产生的角色和肾功能的作用。方法：将进行兴奋毒素病变研究，以确定在特定目标1中鉴定出的PVN和其他CNS位点在Kappa介导的对尿液流，肾脏钠排泄和RSNA的作用中的作用。在单独的实验中，血浆加压素将在患有PVN双侧病变的大鼠中测量。结果：这项研究将提供有关在正常和病理状况下如何相互作用和调节水和钠平衡的基本知识，这对于预防和治疗疾病至关重要。最终，可以开发和用于治疗易感患者的液体过载/低钠血症并改善生活质量。公共卫生相关性：该赠款提案将提供有关阿片类药物和肾功能中心神经肿瘤调节的新的重要信息，并最终为不同心血管和肾脏病理的治疗方式提供新的策略。从这些研究中获得的知识可能会导致开发新的药理学治疗剂来治疗液体和电解质疾病。