Central administration of [Phe(1)Psi(CH2-NH)Gly(2)]nociceptin(1-13)-NH2 and orphanin FQ/nociceptin (OFQ/N) produce similar cardiovascular and renal responses in conscious rats

In vitro studies have shown that [Phe(1)Psi(CH2-NH)Gly(2)]OFQ/N(1-13)-NH2 ( referred to as [FG]OFQ/N(1-13)-NH2) is the first selective antagonist to pr event the binding of the endogenous ligand orphanin FQ/Nociceptin (OFQ/N) a t the orphan opioidlike receptor. In the present study, we examined the pot ential changes in cardiovascular and renal function produced by the i.c.v. injection of [FG]OFQ/N(1-13)-NH2 in conscious Sprague-Dawley rats. In consc ious rats, i.c.v. injection of [FG]OFQ/N(1-13)-NH2 produced a marked and su stained decrease in heart rate, mean arterial pressure, and urinary sodium excretion and a profound increase in urine flow rate (i.e., a water diuresi s). The cardiovascular and renal excretory responses produced by i.c.v. [FG ]OFQ/N(1-13)-NH2 were dose dependent and were similar in pattern but of lon ger duration than responses evoked by i.c.v. OFQ/N. In other animals, the i .c.v. injection of OFQ/ N(1-13)-NH2, a potential metabolite of [FG]OFQ/N(1- 13)-NH2, produced changes in cardiovascular and renal function that were co mparable to those evoked by i.c.v. [FG]OFQ/N(1-13)NH2. In contrast, OFQ/N(2 -17), a fragment of OFQ/N [OFQ/N(1-17)], was inactive when administered cen trally. Finally, studies were performed to determine whether [FG]OFQ/N(I13) -NH2 may be an antagonist at the orphan opioid-like receptor receptor when administered centrally at a dose that alone was inactive. In these studies, i.c.v. pretreatment of animals with low-dose [FG]OFQ/N(1-13)-NH2 failed to prevent the cardiovascular and renal excretory response to i.c.v. OFQ/N. A lthough [FG]OFQ/N(1-13)-NH2 is reported to be an antagonist of the OFQ/N re ceptor in vitro, these findings indicate that this compound has agonist act ivity similar to that of the endogenous ligand OFQ/N when administered cent rally in vivo.