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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana

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.

Address correspondence to: Dr. Zbigniew K. Krowicki, MediProfile, Inc., 1825 Broadway St., New Orleans, LA 70118. E-mail: zkrowi{at}hotmail.com

This article has been cited by other articles:

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