Tonic Nociceptinergic Inputs to Neurons in the Hypothalamic Paraventricular Nucleus Contribute to Sympathetic Vasomotor Tone and Water and Electrolyte Homeostasis in Conscious Rats

摘要

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 [Arg~8]vasopressin (60 fmol/kg/min).Finally,in other studies bilateral microinjection of the NOP receptor antagonist [Nphe~1,Arg~(14),Lys~(15)]N/OFQ-NH_2 (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.