Characterization of [Nphe(1)]nociceptin(1-13)NH2, a new selective nociceptin receptor antagonist

1 Nociceptin (orphanin FQ) is a novel neuropeptide capable of inducing a va riety of biological actions via activation of a specific G-protein coupled receptor. However, the lack of a selective nociceptin receptor antagonist h as hampered our understanding of nociceptin actions and the role of this pe ptide in pathophysiological states. As part of a broader programme of resea rch, geared to the identification and characterization of nociceptin recept or ligands, we report that the novel peptide [Nphe(1)]nociceptin(1-13)NH2 a cts as the first truly selective and competitive nociceptin receptor antago nist and is devoid of any residual agonist activity. 2 [Nphe(1)]nociceptin(1-13)NH2 binds selectively to recombinant nociceptin receptors expressed in Chinese hamster ovary (CHO) cells (pK(i) 8.4) and co mpetitively antagonizes the inhibitory effects of nociceptin (i) on cyclic AMP accumulation in CHO cells (pA(2) 6.0) and (ii) on electrically evoked c ontractions in isolated tissues of the mouse, rat and guinea-pig with pA(2) values ranging from 6.0 to 6.4. 3 [Nphe(1)]nociceptin(1-13)NH2 is also active in vivo, where it prevents th e pronociceptive and antimorphine actions of intracerebroventricularly appl ied nociceptin, measured in the mouse tail withdrawal assay. Moreover, [Nph e(1)]nociceptin(1-13)NH2 produces per se a dose dependent, naloxone resista nt antinociceptive action and, at relatively low doses, potentiates morphin e-induced analgesia. 4 Collectively our data indicate that [Nphe(1)]nociceptin(1-13)NH2, acting as a nociceptin receptor antagonist, may be the prototype of a new class of analgesics.