Comparison of the effects of [Phe 1 Ψ(CH 2 ‐NH)Gly 2 ]Nociceptin (1–13)NH 2 in rat brain, rat vas deferens and CHO cells expressing recombinant human nociceptin receptors

Nociceptin(NC) is the endogenous ligand for the opioid receptor like‐1 receptor (NC‐receptor). [Phe 1 ΨC(CH 2 ‐NH)Gly 2 ]Nociceptin(1–13)NH 2 ([F/G]NC(1–13)NH 2 ) has been reported to antagonize NC actions in peripheral guinea‐pig and mouse tissues. In this study, we investigated the effects of a range of NC C‐terminal truncated fragments and [F/G]NC(1–13)NH 2 on NC receptor binding, glutamate release from rat cerebrocortical slices (rCX), inhibition of cyclic AMP accumulation in CHO cells expressing the NC receptor (CHO NCR ) and electrically evoked contractions of the rat vas deferens (rVD). In radioligand binding assays, a range of ligands inhibited [ 125 I]‐Tyr 14 ‐NC binding in membranes from rCX and CHO NCR cells. As the peptide was truncated there was a general decline in pK i . [F/G]NC(1–13)NH 2 was as potent as NC(1–13)NH 2 . The order of potency for NC fragments to inhibit cyclic AMP accumulation in whole CHO NCR cells was NCNH 2 NC=NC(1–13)NH 2 >NC(1–12)NH 2 >>NC(1–11)NH 2 . [F/G]NC(1–13)NH 2 was a full agonist with a pEC 50 value of 8.65. NCNH 2 and [F/G]NC(1–13)NH 2 both inhibited K + evoked glutamate release from rCX with pEC 50 and maximum inhibition of 8.16, 48.5±4.9% and 7.39, 58.9±6.8% respectively. In rVD NC inhibited electrically evoked contractions with a pEC 50 of 6.63. Although [F/G]NC(1–13)NH 2 , displayed a small (instrinsic activity α=0.19) but consistent residual agonist activity, it acted as a competitive antagonist (pA 2 6.76) in the rVD. The differences between [F/G]NC(1–13)NH 2 action on central and peripheral NC signalling could be explained if [F/G]NC(1–13)NH 2 was a partial agonist with high strength of coupling in the CNS and low in the periphery. An alternative explanation could be the existence of central and peripheral receptor isoforms. British Journal of Pharmacology (1999) 127 , 123–130; doi: 10.1038/sj.bjp.0702539