Intracerebroventricular (i.c.v.) nociceptin/orphanin FQ (N/OFQ) produces cardiovascular depressor, diuretic and renal sympathoinhibitory responses in conscious rats. These studies examined how a chronic high NaCl intake alters these peptide-evoked responses and the activity of the endogenous central N/OFQ-NOP receptor system. In normotensive Sprague-Dawley rats that were fed a chronic (3 week) high (8%) NaCl diet, i.c.v. N/OFQ (5.5 nmol) produced prolonged bradycardic, hypotensive and diuretic responses, but failed to suppress renal sympathetic nerve activity. In a separate group of rats maintained on a high NaCl diet, i.c.v. infusion of the NOP receptor antagonist, UFP-101, significantly decreased urine output. At the tissue level, high NaCl treatment of rats significantly increased NOP receptor density, without altering endogenous N/OFQ peptide levels in whole hypothalamus (control, 712±35 fmol/mg vs. 8% NaCl, 883±49 fmol/mg, P<0.05) and paraventricular nucleus (PVN). Further, in the hypothalamus, basal GTPS binding was increased without altering the sensitivity of N/OFQ stimulated G-protein coupling. In contrast, in whole medulla and the ventrolateral medulla (VLM), high NaCl treatment decreased NOP receptor density (medulla; control, 1473±131 fmol/mg vs. 8% NaCl, 327±31 fmol/mg, P<0.05) and endogenous N/OFQ peptide levels (medulla; control, 35.3±2 fmol/mg vs. 8% NaCl, 11.9±3 fmol/mg, P<0.05), while increasing the sensitivity of G-protein signaling pathways to N/OFQ stimulation. Together, these findings suggest that during a chronic high salt intake, regional changes in the activity of the N/OFQ-NOP system in the brain may contribute to the tonic regulation of cardiovascular function and urine output, and to the altered physiological responses to exogenous central N/OFQ.