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.
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.
