Nociceptin is an endogenous ligand of the opioid receptor-like (ORL1) receptor, 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 understood. The main aim of this investigation was to study the effects of nociceptin and the putative ORL1 receptor antagonist [Phe 1ψ(CH 2-NH)Gly 2]nociceptin(1–13)NH 2 in two peripheral tissues, the isolated proximal colon of the mouse and the distal colon of the rat. Nociceptin, [ d-Ala 2, MePhe 4, Gly-ol 5]enkephalin (DAMGO; μ-opioid receptor selective) and [ d-Pen 2, d-Pen 5]enkephalin (DPDPE; δ-opioid receptor selective) caused concentration-dependent contractions of mouse and rat isolated colon preparations (nociceptin EC 50=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) antagonised the effects of DAMGO and DPDPE but had no effect in either preparation on contractions seen in response to nociceptin. [Phe 1ψ(CH 2-NH)Gly 2]nociceptin(1–13)NH 2 also caused contractions in the colonic preparations (EC 50=6.0 and 3.1 nM in the mouse and rat, respectively); there was no evidence of any antagonist activity. Tetrodotoxin (1 μM) abolished the contractile 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 caused concentration-dependent inhibitions of electrically-evoked contractions which were antagonised by [Phe 1ψ(CH 2-NH)Gly 2]nociceptin(1–13)NH 2 (apparent p K B=6.31). However, [Phe 1ψ(CH 2-NH)Gly 2]nociceptin(1–13)NH 2 (0.3–10 μM) also possessed agonist activity in this preparation, as it inhibited the electrically-evoked contractions in a concentration-dependent manner. These observations do not support the proposal that [Phe 1ψ(CH 2-NH)Gly 2]nociceptin(1–13)NH 2 has agonist activity at central ORL1 receptors but is an antagonist in the periphery and that these differences in efficacy point to differences in the receptors. Rather, these data along with those of others suggest that [Phe 1ψ(CH 2-NH)Gly 2]nociceptin(1–13)NH 2 is a partial agonist and that differences in receptor reserve can account for the varied pharmacological actions of this pseudopeptide at central and peripheral sites.
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