TY - JOUR T1 - Tonic Nociceptinergic Inputs to Neurons in the Hypothalamic Paraventricular Nucleus Contribute to Sympathetic Vasomotor Tone and Water and Electrolyte Homeostasis in Conscious Rats JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 446 LP - 453 DO - 10.1124/jpet.105.094441 VL - 317 IS - 1 AU - Zbigniew K. Krowicki AU - Daniel R. Kapusta Y1 - 2006/04/01 UR - http://jpet.aspetjournals.org/content/317/1/446.abstract N2 - Central administration of nociceptin/orphanin FQ (N/OFQ) produces bradycardia, hypotension, diuresis, and antinatriuresis in rats. Because N/OFQ peptide (NOP) receptors exist in the paraventricular nucleus (PVN) of the hypothalamus, we hypothesized that N/OFQ acts in the PVN to alter cardiovascular and renal function. To test this premise, N/OFQ (10 and 100 pmol) or artificial cerebrospinal fluid (vehicle) was microinjected into the right PVN of conscious, chronically instrumented rats infused i.v. with isotonic saline. After injection, N/OFQ, but not vehicle, dose-dependently decreased renal sympathetic nerve activity (RSNA) and increased urine flow rate. At 100 pmol, N/OFQ also decreased urinary sodium and potassium excretion and increased free water clearance. In separate groups, the diuretic response to N/OFQ injection into the PVN was blunted in chronic bilaterally renal denervated rats and abolished in intact rats continuously infused i.v. with [Arg8]vasopressin (60 fmol/kg/min). Finally, in other studies bilateral microinjection of the NOP receptor antagonist [Nphe1,Arg14,Lys15]N/OFQ-NH2 (UFP-101; 300 pmol) into the PVN increased heart rate and RSNA and decreased urine flow rate without altering electrolyte excretion. Pretreatment of separate rats with UFP-101 (300 pmol, PVN) blocked the N/OFQ-evoked (100 pmol) cardiovascular, renal sympathetic nerve, and renal excretory responses. Together, these findings demonstrate that in conscious rats activation of NOP receptors in the PVN by N/OFQ produces bradycardia, renal sympathoinhibition, and water diuresis. Moreover, UFP-101 blocks a tonically active inhibitory influence of endogenous N/OFQ on central sympathetic outflow and vasopressin pathways which arise from the PVN to affect heart rate and urine output. The American Society for Pharmacology and Experimental Therapeutics ER -