Abstract
In vitro studies have shown that [Phe1Ψ(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)-NH2produced 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.
Footnotes
-
Send reprint requests to: Daniel R. Kapusta, Ph.D., Department of Pharmacology, Louisiana State University Medical Center, 1901 Perdido St., New Orleans, LA 70112. E-mail: dkapus{at}lsumc.edu
-
↵1 This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-43337 and American Heart Association, Louisiana Affiliate, Grant 91-6-08B (to D.R.K.).
- Abbreviations:
- CNS
- central nervous system, OFQ/N, orphanin FQ/nociceptin, [FG]OFQ/N(1–13)-NH2, [Phe1Ψ(CH2-NH)Gly2]OFQ/N(1–13)-NH2, ORL1, opioid receptor-like 1
- Received July 1, 1998.
- Accepted November 4, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|