Central Kappa Opioid Neural Regulation of Cardiovascular and Renal Function

在某些病理生理状态下（如肝硬化伴腹水），动脉循环完整性的改变可通过中枢神经系统和外周神经和体液机制的激活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产生低钠血症、肺充血和最终死亡。中枢阿片类kappa的激活产生明显的水利尿（尿流量增加，但肾脏钠排泄不同时增加），这与迄今为止临床使用的传统利尿剂（增强水和钠排泄）不同。目的：这些研究的目的是确定中枢阿片系统调节正常和肝硬化大鼠肾功能的中枢神经系统部位和神经通路。研究问题：什么是中枢神经系统机制和途径负责阿片类药物介导的肾效应？以下具体目标将被解决：1)确定中枢阿片系统激活产生利尿、抗尿和RSNA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研究将确定正常和肝硬化大鼠中kappa阿片受体激动剂（ICV）直接调节的中枢神经系统部位。Western Blot分析将确定这些区域的kappa阿片受体和肽蛋白水平。逆行通道追踪将用于确定可能影响PVN旁细胞活性的区域，以及表达cFos和/或ICER的区域。2)确定PVN旁细胞神经元和相关中枢神经系统位点在阿片类kappa中枢激活产生的心血管和肾脏功能中的作用。方法：将进行兴奋毒素病变研究，以确定PVN和特异性Aim 1中确定的其他CNS部位在kappa介导的尿流、肾钠排泄和RSNA影响中的作用。在单独的实验中，将测量双侧PVN病变大鼠的血浆加压素。结果：本研究将为正常和病理条件下不同系统如何相互作用和调节水钠平衡提供基础知识，这对疾病的预防和治疗至关重要。最终，阿片类化合物可以开发并用于治疗易感患者的液体过载/低钠血症，并改善患者的生活质量。

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.