RT Journal Article
SR Electronic
T1 [Nphe<sup>1</sup>]NC(1-13)NH<sub>2</sub> Selectively Antagonizes Nociceptin/Orphanin FQ-Stimulated G-Protein Activation in Rat Brain
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 428
OP 433
VO 294
IS 2
A1 Hartmut Berger
A1 Girolamo Calo'
A1 Erika Albrecht
A1 Remo Guerrini
A1 Michael Bienert
YR 2000
UL http://jpet.aspetjournals.org/content/294/2/428.abstract
AB [Phe1psi(CH2-NH)Gly2]noc/OFQ(1-13)-amide {[F/G]NC(1-13)NH2} and acetyl-RYYRIK-amide (Ac-RYYRIK-NH2), two peptidic ligands of the nociceptin/orphanin FQ (noc/OFQ) receptor, have been shown to exert both agonist and antagonist activity in different in vitro and in vivo systems. This is despite the observation that both peptides competitively antagonized the coupling of the activated receptor to G-proteins in brain preparations, measured in GTPγ35S binding assays. In this study, [Nphe1]NC(1-13)-amide ([Nphe1]NC(1-13)NH2), a new noc/OFQ analog recently characterized as a pure and selective noc/OFQ receptor antagonist in several in vitro and in vivo assay systems, was shown to competitively inhibit the noc/OFQ-stimulated GTPγ35S binding to rat cerebral cortex membranes with pA2 of 7.76 (Schild analysis). This antagonism of noc/OFQ receptor G-protein coupling was selective because the peptide inhibited the noc/OFQ-evoked GTPγ35S binding to rat brain membranes but not that evoked by selective agonists of the μ-, δ-, and κ-opioid receptors. In rat cortical membranes, the effects of [F/G]NC(1-13)NH2 and Ac-RYYRIK-NH2 on the binding of GTPγ35S were clearly differentiated from the effect of [Nphe1]NC(1-13)NH2 when the concentration of GDP, competing with GTPγS for binding, was lowered from 100 μM (assay optimum) to 5 μM. At 5 μM GDP, the former peptides showed clear partial agonist activity, whereas [Nphe1]NC(1-13)NH2 did not. These data indicate that only [Nphe1]NC(1-13)NH2 was a pure antagonist of noc/OFQ receptor G-protein coupling. Furthermore, it is suggested that the variable behavior of [F/G]NC(1-13)NH2 and Ac-RYYRIK-NH2 (agonist, partial agonist, and antagonist) in different in vitro and in vivo systems may be explained by different partial GTP binding agonism and the existence of a GTP binding stimulus/response reserve (coupling reserve). The American Society for Pharmacology and Experimental Therapeutics