Centrally administered nociceptin/orphanin FQ (N/OFQ) evokes bradycardia, hypotension, and diuresis in mice via activation of central N/OFQ peptide receptors

The present studies examined the cardiovascular and renal responses produced by activation of central nociceptin/ orphanin FQ ( N/ OFQ) peptide ( NOP) receptors in conscious mice. To assess this, we examined changes in heart rate ( HR), mean arterial pressure ( MAP), urine output ( V), urinary sodium excretion ( UNaV), and free water clearance ( CH2O) produced by acute i.c.v. injection of N/OFQ ( 0.03, 0.3, 1, or 3 nmol) or isotonic saline vehicle ( 2 mu l) in conscious telemetered ICR-CD1 mice. After i.c.v. injection, N/ OFQ, but not vehicle, dose dependently decreased HR and MAP and increased V. At 3 nmol, N/ OFQ reduced HR [ control ( C), 672 +/- 23 beats/ min; 20 min, 411 +/- 30 beats/ min] and MAP ( C, 108 +/- 4 mm Hg; 20 min, 62 +/- 6 mm Hg). In the same telemetered mice, i.c.v. N/ OFQ significantly elevated V ( 0.65 +/- 0.03 cc/ 2 h) compared with levels for the vehicle- treated group ( 0.15 +/- 0.09 cc/ 2 h). Central N/ OFQ/ vehicle did not alter UNaV or CH2O. In separate studies, 2- h i.c.v. pretreatment with the NOP receptor antagonist UFP101 ([ Nphe(1), Arg(14), Lys(15)] N/ OFQ- NH2) ( 10 or 30 nmol) markedly, but transiently, reduced HR but not MAP, V, UNaV, or CH2O. After 2- h UFP- 101 ( 10 or 30 nmol) pretreatment, subsequent i.c.v. injection of N/OFQ ( 1 or 3 nmol) failed to alter cardiovascular or renal function. In contrast, in separate mice, 2- h pretreatment with N/ OFQ ( 1 or 3 nmol) or vehicle failed to prevent the cardiodepressor and diuretic responses to a subsequent i. c. v. injection of the same dose of N/ OFQ. Together, these findings demonstrate that in conscious mice, the central administration of N/ OFQ evokes marked bradycardia, hypotension, and diuresis by selective activation of central NOP receptors.