In vitro agonist effects of nociceptin and [Phe1 psi(CH2-NH)Gly(2)]nociceptin(1-13)NH2 in the mouse and rat colon and the mouse vas deferens

Nociceptin is an endogenous ligand of the opioid receptor-like (ORL1) recep tor, a G-protein coupled receptor with sequence similarities to the opioid receptors. ORL1 receptors are present at both central and peripheral sites in several mammalian species but their functions are as yet poorly understo od. The main aim of this investigation was to study the effects of nocicept in and the putative ORL1 receptor antagonist [Phe(1)psi(CH2-NH)Gly(2)]nocic eptin(1-13)NH2 in two peripheral tissues, the isolated proximal colon of th e mouse and the distal colon of the rat. Nociceptin, [D-Ala(2), MePhe(4), G ly-ol(5)]enkephalin (DAMGO; mu-opioid receptor selective) and [D-Pen(2), D- Pen(5)]enkephalin (DPDPE; delta-opioid receptor selective) caused concentra tion-dependent contractions of mouse and rat isolated colon preparations (n ociceptin EC50 = 1.20 and 0.28 nM in the mouse and rat, respectively). Des[ Phe(1)]nociceptin (250 nM) had no contractile effect. Naloxone (300 nM) ant agonised the effects of DAMGO and DPDPE but had no effect in either prepara tion on contractions seen in response to nociceptin. [Phe(1)psi(CH2-NH)Gly( 2)]nociceptin(1-13)NH2 also caused contractions in the colonic preparations (EC50 = 6.0 and 3.1 nM in the mouse and rat, respectively); there was no e vidence of any antagonist activity. Tetrodotoxin (1 mu M) abolished the con tractile effects of nociceptin in the mouse colon but had no effect in the rat. In the vas deferens preparation isolated from DBA/2 mice, nociceptin c aused concentration-dependent inhibitions of electrically-evoked contractio ns which were antagonised by [Phe(1)psi(CH2-NH)Gly(2)]nociceptin(1-13)NH2 ( apparent pK(B) = 6.31). However, [Phe(1)psi(CH2-NH)Gly(2)]nociceptin(1-13)N H2 (0.3-10 mu M) also possessed agonist activity in this preparation, as it inhibited the electrically-evoked contractions in a concentration-dependen t manner. These observations do not support the proposal that [Phe(1)psi(CH 2-NH)Gly(2)]nociceptin(1-13)NH2 has agonist activity at central ORL1 recept ors but is an antagonist in the periphery and that these differences in eff icacy point to differences in the receptors. Rather, these data along with those of others suggest that [Phe(1)psi(CH2-NH)Gly(2)]nociceptin(1-13)NH2 i s a partial agonist and that differences in receptor reserve can account fo r the varied pharmacological actions of this pseudopeptide at central and p eripheral sites. (C) 1999 Elsevier Science B.V. All rights reserved.