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Vol. 289, Issue 1, 173-180, April 1999
(CH2-NH)Gly2]Nociceptin(1-13)-NH2
and Orphanin FQ/Nociceptin (OFQ/N) Produce Similar Cardiovascular and
Renal Responses in Conscious Rats1
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.
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