Abstract
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 ΔHR = -217 ± 31 bpm; peak ΔMAP =-47 ± 7 mm Hg) compared with saline (peak ΔHR =-14 ± 5 bpm; peak ΔMAP = 2 ± 3 mm Hg). These N/OFQ-evoked bradycardic and hypotensive responses were absent in NOP-/- (peak ΔHR =-13 ± 17 bpm; peak ΔMAP =-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.
Footnotes
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This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (Grants DK-43337 and DK-02605 to D.R.K.) and by the Heart Blood and Lung Institute (Grant HL71212 to D.R.K.). Additional funding for this work was provided to the Cardiac and Vascular Core Facility in the Department of Pharmacology and Center of Excellence in Cardiovascular Research at Louisiana State University Health Sciences Center by COBRE Grant P20 RR018766 (to D.R.K.) from the National Center for Research Resources, a component of the National Institutes of Health.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.135905.
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ABBREVIATIONS: N/OFQ, nociceptin/orphanin FQ; NOP, nociceptin/orphanin FQ peptide; HR, heart rate; MAP, mean arterial pressure; UFP-101, [Nphe1,Arg14,Lys15]N/OFQ-NH2; NOP-/-, NOP receptor knockout; NOP+/+, NOP receptor wild-type; V, urine output; UNaV, urinary sodium excretion; UKV, urinary potassium excretion; CH20, free water clearance.
- Received December 22, 2007.
- Accepted June 4, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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