Central Kappa Opioid Neural Regulation of Cardiovascular and Renal Function

描述(申请人提供)：在某些病理生理状态(例如，有腹水的肝硬化)，动脉循环完整性的改变可通过激活中枢神经系统和外周的神经和体液机制，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会导致低钠血症、肺充血和最终死亡。中枢kappa阿片类药物的激活会产生显著的利水作用(尿流量增加，但不会同时增加肾脏的钠排泄)，这与迄今为止临床上使用的传统利尿剂不同(它增加了水和钠的排泄)。目的：这些研究的目的是确定中枢kappa阿片系统调节正常和肝硬变大鼠肾功能的中枢神经系统部位和神经通路。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？具体目标如下：1)确定中枢kappa阿片系统激活所产生的利尿剂、抗心钠剂和RSNA所涉及的中枢神经系统区域。方法：RNA原位杂交组织化学结合CFOS或ICER研究，将确定正常大鼠和肝硬变大鼠中哪些中枢神经系统部位直接受到kappa阿片激动剂(ICV)的调节。Western Blot分析将确定这些区域的kappa阿片受体和多肽蛋白水平。逆行追踪将被用来确定可能影响微小细胞PVN活性和表达CFos和/或ICER的区域2)确定PVN微小细胞神经元和相关的CNS位置在中枢激活kappa阿片类药物所产生的心血管和肾功能中的作用。方法：通过激毒素损伤研究，确定PVN和其他特定目标1中确定的中枢神经系统位点在kappa介导的尿流、肾钠排泄和RSNA效应中的作用。在单独的实验中，将测量双侧PVN损伤的大鼠的血浆加压素。结果：这项研究将提供不同系统在正常和病理条件下如何相互作用和调节水和钠平衡的基本知识，这对疾病的预防和治疗至关重要。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超负荷/低钠血症，并改善一个人的生活质量。 与公共卫生相关：这项赠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，并最终将为不同心血管和肾脏疾病的治疗方式提供新的战略。从这些研究中获得的知识可能会导致新的药物治疗剂的开发，用于治疗液体和电解质紊乱。

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.