Vol. 289, Issue 1, 173-180, April 1999

Central Administration of [Phe¹(CH₂-NH)Gly²]Nociceptin(1-13)-NH₂ and Orphanin FQ/Nociceptin (OFQ/N) Produce Similar Cardiovascular and Renal Responses in Conscious Rats¹

Daniel R. Kapusta, Jaw-Kang Chang and Velga A. Kenigs

Department of Pharmacology and Experimental Therapeutics, Louisiana State University Medical Center, New Orleans, Louisiana (D.R.K., V.A.K.); and Phoenix Pharmaceuticals Inc., Mountain View, California (J.-K.C.)

In vitro studies have shown that [Phe¹(CH₂-NH)Gly²]OFQ/N(1-13)-NH₂ (referred to as [FG]OFQ/N(1-13)-NH₂) is the first selective antagonist to prevent the binding of the endogenous ligand orphanin FQ/Nociceptin (OFQ/N) at the orphan opioid-like receptor. In the present study, we examined the potential 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 conscious rats, i.c.v. injection of [FG]OFQ/N(1-13)-NH₂ produced a marked and sustained decrease in heart rate, mean arterial pressure, and urinary sodium excretion and a profound increase in urine flow rate (i.e., a water diuresis). 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 longer 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 comparable 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 centrally. Finally, studies were performed to determine whether [FG]OFQ/N(1-13)-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. Although [FG]OFQ/N(1-13)-NH₂ is reported to be an antagonist of the OFQ/N receptor in vitro, these findings indicate that this compound has agonist activity similar to that of the endogenous ligand OFQ/N when administered centrally in vivo.