Comparison of the effects of [Phe(1)Psi(CH2-NH)Gly(2)]nociceptin (1-13)NH2in rat brain, rat vas deferens and CHO cells expressing recombinant human nociceptin receptors

1 Nociceptin(NC) is the endogenous ligand for the opioid receptor like-1 re ceptor (NC-receptor). [Phe'Psi(CH2-NH)Gly(2)]Nociceptin(1-13)NH2 ([F/G]NC(1 -13)NH2) has been reported to antagonize NC actions in peripheral guinea-pi g 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)NH2 on NC receptor bi nding, glutamate release from rat cerebrocortical slices (rCX), inhibition of cyclic AMP accumulation in CIIO cells expressing the NC receptor (CHONCR ) and electrically evoked contractions of the rat vas deferens (rVD). 2 In radioligand binding assays, a range of ligands inhibited [I-125]-Tyr(1 4)-NC binding in membranes from rCX and CHONCR cells. As the peptide was tr uncated there was a general decline in pK(i). [F/G]NC(1-13)NH2 was as poten t as NC(1-13)NH2. 3 The order of potency for NC fragments to inhibit cyclic AMP accumulation in whole CHONCR cells was NCNH2 greater than or equal to NC = NC(1-13)NH2 > NC(1-12)NH2 > > NC(1-11)NH2. [F/G]NC(1-13)NH2 was a full agonist with a pE C(50) value of 8.65. 4 NCNH2 and [F/G]NC(1-13)NH2 both inhibited K+ evoked glutamate release fro m rCX with pEC(50) and maximum inhibition of 8.16, 48.5+/-4.9% and 7.39, 58 .9+/-6.8% respectively. 5 In rVD NC inhibited electrically evoked contractions with a pEC(50) of 6. 63. Although [F/G]NC(1-13)NH2, displayed a small (instrinsic activity alpha =0.19) but consistent residual agonist activity, it acted as a competitive antagonist (pA(2) 6.76) in the rVD. 6 The differences between [F/G]NC(1-13)NH2 action on central and peripheral NC signalling could be explained if [F/G]NC(1-13)NH2 was a partial agonist with high strength of coupling in the CNS and low in the periphery. An alt ernative explanation could be the existence of central and peripheral recep tor isoforms.