Nociceptin/orphanin FQ (N/OFQ)-evoked bradycardia, hypotension, and diuresis are absent in N/OFQ peptide (NOP) receptor knockout mice.
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 DeltaHR = -217 +/- 31 bpm; peak DeltaMAP =-47 +/- 7 mm Hg) compared with saline (peak DeltaHR =-14 +/- 5 bpm; peak DeltaMAP = 2 +/- 3 mm Hg). These N/OFQ-evoked bradycardic and hypotensive responses were absent in NOP(-/-) (peak DeltaHR =-13 +/- 17 bpm; peak DeltaMAP =-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.
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Melissa A
MA
Burmeister
Michael A
MA
Ansonoff
John E
JE
Pintar
Daniel R
DR
Kapusta
D000818:Animals; D001919:Bradycardia / Q000139:chemically induced / Q000378:metabolism*; D004231:Diuresis / Q000187:drug effects / Q000502:physiology*; D007022:Hypotension / Q000139:chemically induced / Q000378:metabolism*; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018847:Opioid Peptides / Q000008:administration & dosage* / Q000172:deficiency* / Q000235:genetics; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism*; D000097629:Nociceptin
D018847:Opioid Peptides; D011957:Receptors, Opioid; D000097629:Nociceptin