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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Nociceptin/Orphanin FQ (N/OFQ)-Evoked Bradycardia, Hypotension, and Diuresis Are Absent in N/OFQ Peptide (NOP) Receptor Knockout Mice

Departments of Pharmacology and Experimental Therapeutics (M.A.B., D.R.K.) and Anesthesiology (D.R.K.) and the Cardiovascular Center of Excellence (D.R.K.), Louisiana State University Health Sciences Center, New Orleans, Louisiana; and Department of Neuroscience, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey (M.A.A., J.E.P.)

Intracerebroventricular administration of the opioid-like peptide nociceptin/orphanin FQ (N/OFQ) produces bradycardia, hypotension, and diuresis in mice. We hypothesized that these responses are solely caused by selective activation of central N/OFQ peptide (NOP) receptors. To test this premise, we first examined whether i.c.v. N/OFQ produced dose-dependent diuretic and cardiovascular depressor responses in commercially available C57BL/6 mice. Next, using doses established in these studies, we examined the renal excretory and cardiovascular responses to i.c.v. N/OFQ in conscious transgenic NOP receptor knockout mice (NOP^-/-). In metabolic studies, i.c.v. N/OFQ, but not saline vehicle, dose-dependently increased urine output (V) in NOP^+/+; this response was significant at 3 nmol (N/OFQ, V = 0.39 ± 0.10 ml/2 h; saline, 0.08 ± 0.05 ml/2 h). The N/OFQ-evoked diuresis was absent in littermate NOP^-/- (N/OFQ, V = 0.06 ± 0.06 ml/2 h; saline, 0.03 ± 0.03 ml/2 h). There were no significant changes in urinary sodium or potassium excretion or free water clearance in either group. In telemetry studies, i.c.v. N/OFQ dose dependently lowered heart rate (HR) and mean arterial pressure (MAP). At 3 nmol N/OFQ, both HR and MAP were reduced in NOP^+/+ (peak HR = -217 ± 31 bpm; peak MAP =-47 ± 7 mm Hg) compared with saline (peak HR =-14 ± 5 bpm; peak MAP = 2 ± 3 mm Hg). These N/OFQ-evoked bradycardic and hypotensive responses were absent in NOP^-/- (peak HR =-13 ± 17 bpm; peak MAP =-2 ± 4 mm Hg, respectively). Basal 24-h cardiovascular and renal excretory function were not different between NOP^-/- and NOP^+/+ mice. These results establish that the bradycardia, hypotension and diuresis produced by centrally administered N/OFQ are mediated by selective activation of NOP receptors.

Address correspondence to: Dr. Daniel R. Kapusta, Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112. E-mail: dkapus{at}lsuhsc.edu