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

• 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
• 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

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下（例如，腹水型糖尿病），动脉循环完整性的变化可通过激活CNS和外周的神经元和体液机制导致肾脏液体和电解质排泄的深刻变化。这些系统的慢性激活可导致低钠血症、肺充血和最终死亡。中枢κ阿片样物质的激活产生明显的水利尿（尿流量增加，但同时肾钠排泄增加），这不同于迄今为止临床上使用的传统利尿剂（其增强水和钠排泄）。目的：这些研究的目的是确定中枢kappa阿片系统调节正常和肾病大鼠肾功能的CNS位点和神经通路。研究问题：kappa阿片类药物介导的肾脏效应的中枢神经系统机制和途径是什么？将讨论以下具体目的：1）确定中枢κ阿片系统激活产生的利尿剂、抗心房利尿剂和RSNA所涉及的CNS区域。研究方法：RNA原位杂交组织化学结合cFos或ICER研究将确定哪些CNS位点在正常和痴呆大鼠中被κ阿片受体激动剂（ICV）直接调节。蛋白质印迹分析将确定这些区域的kappa阿片受体和肽蛋白水平。逆行束示踪将用于鉴定可能影响小细胞PVN活性并且还表达cFos和/或ICER的区域2）确定PVN小细胞神经元和相关CNS位点对由κ阿片样物质的中枢激活产生的心血管和肾功能的作用。研究方法：将进行兴奋性毒素损伤研究，以确定PVN和特定目的1中确定的其他CNS位点在对尿流量、肾钠排泄和RSNA的κ介导效应中的作用。在单独的实验中，将在PVN双侧病变的大鼠中测量血浆加压素。成果：这项研究将提供关于不同系统如何在正常和病理条件下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，阿片类化合物可以被开发并用于治疗易感患者的液体过载/低钠血症和改善生活质量。 公共卫生关系：这项拨款提案将提供有关阿片类药物和肾功能中枢神经体液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导致开发用于治疗体液和电解质紊乱的新药理学治疗剂。