The nociceptin/orphanin FQ receptor ligand acetyl-RYYRIK-amide exhibits antagonistic and agonistic properties

The hexapeptide acetyl-RYYRIK-amide (Ac-RYYRIK-NH2) has recently been repor ted to act as partial agonist of the nociceptin/orphanin FQ (noc/OFQ) recep tor expressed in CHO cells. In addition, this peptide acts as a competitive antagonist of noc/OFQ-stimulated GTP gamma(35)S binding in rat brain membr anes as well as of the noc/OFQ-evoked chronotropic effect in rat cardiomyoc ytes. In contrast to this antagonism, in the present study, Ac-RYYRIK-NH2 w as found to behave as an agonist at noc/OFQ receptors, affecting spontaneou s locomotor activity. When administered intracerebroventricularly (i.c.v.), noc/OFQ and Ac-RYYRIK-NH2 inhibited spontaneous locomotor activity in mice with ID50 of 1.1 and 0.07 nmol, respectively. Co-administration of both pe ptides lead to additive effects. The higher potency of Ac-RYYRIK-NH2 could not be clearly explained by differential metabolism, because in vivo microd ialysis in rat striatum and in vitro metabolic inactivation by rat and mous e brain membranes revealed extensive inactivation of both peptides. Similar to Ac-RYYRIK-NH2, [Phe(1)psi(CH2-NH)Gly(2)]noc/OFQ(1-13)-NH2 ([F/G]NC(1-13 )NH2) inhibited the nociOFQ-stimulated GTP gamma(35)S binding in rat brain membranes (Schild constant 3.83 nM) and mouse brain sections, although seve ral reports have shown that this peptide exhibits agonist activity of noc/O FQ in the CNS. Changes in the optimum conditions of the in vitro assay for GTP binding increased low partial agonism of Ac-RYYRIK-NH2 in GTP binding r esponse. To explain the discrepancy between the in vitro antagonism of G pr otein coupling of the noc/OFQ receptor and in vivo agonism of Ac-RYYRIK-NH2 and of [F/G]NC(1-13)NH2, it is suggested that low par rial agonism of rece ptor/G protein coupling in native systems may be sufficient to evoke full b iologic responses. The extent of partial agonism for GTP binding and of cou pling reserve may vary in different systems, thus explaining why [FIG]NC(1- 13)NH2 and Ac-RYYRIK-NH2 were reported to exhibit antagonist, partial agoni st, or even full agonist properties, depending on the system studied. (C) 2 000 Elsevier Science Inc. All rights reserved.