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 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.