CNS sites involved in the cardiovascular and renal effects of nociceptin in rats with heart failure

In vivo studies in conscious animals indicate that ORL1, for opioid receptor-like one, receptor agonists produce profound changes in the cardiovascular function and renal excretion of water and sodium via an action within the central nervous system (CNS). These observations provide evidence to suggest that central endogenous ORL1 receptors participate in the regulation of cardiovascular and renal function under normal and certain pathophysiological conditions. In regard to endogenous systems, opioid peptides have been categorized into three major families, β-endorphins, enkephalins and dynorphins, and are suggested to be the endogenous ligands for the mu-, delta- and kappa-opioid receptors, respectively. In addition to these subtypes, a fourth opioid receptor termed ORL1 has been identified. The endogenous ligand for the ORL1 receptor has been isolated and is a novel endogenous peptide referred to as nociceptin (N/OFQ). Despite their structural resemblance to endogenous opioid peptides and receptors, the role of nociceptin and the ORL1 receptor in pathophysiological (e.g., heart failure) regulatory processes including the regulation of cardiovascular and renal function, is not known. Activation of ORL1 receptors in conscious healthy rats produce bradycardia, hypotension, and a free water diuresis (increase in excretory urine flow rate without concurrent increase in sodium excretion). In addition, this diuretic effect occurs without the loss of potassium. As such, nociceptin produces pharmacological effects that are similar to the combined effect of several drugs currently used to treat heart failure (e.g., ACE inhibitors, beta blockers, and diuretics). Thus, nociceptin is a potential candidate for the treatment of this disease. However, the sites, mechanism and pathways involved in these responses are unknown. Furthermore, the effects of nociceptin in a heart failure model are still to be established. Proposed experiments are designed to examine the changes produced by selective activation of ORL1 receptors in a heart failure model. The results of these studies will provide fundamental knowledge of how an individual component of the opioid system affects cardiovascular and renal function. This is of importance because the development of novel therapeutics with affinity for a specific opioid receptor subtype will require further investigation under different experimental and pathophysiological conditions.