Characterization of [Nphe 1 ]nociceptin(1‐13)NH 2 , a new selective nociceptin receptor antagonist

Nociceptin (orphanin FQ) is a novel neuropeptide capable of inducing a variety of biological actions via activation of a specific G‐protein coupled receptor. However, the lack of a selective nociceptin receptor antagonist has hampered our understanding of nociceptin actions and the role of this peptide in pathophysiological states. As part of a broader programme of research, geared to the identification and characterization of nociceptin receptor ligands, we report that the novel peptide [Nphe 1 ]nociceptin(1‐13)NH 2 acts as the first truly selective and competitive nociceptin receptor antagonist and is devoid of any residual agonist activity. [Nphe 1 ]nociceptin(1‐13)NH 2 binds selectively to recombinant nociceptin receptors expressed in Chinese hamster ovary (CHO) cells (p K i 8.4) and competitively antagonizes the inhibitory effects of nociceptin (i) on cyclic AMP accumulation in CHO cells (pA 2 6.0) and (ii) on electrically evoked contractions in isolated tissues of the mouse, rat and guinea‐pig with pA 2 values ranging from 6.0 to 6.4. [Nphe 1 ]nociceptin(1‐13)NH 2 is also active in vivo , where it prevents the pronociceptive and antimorphine actions of intracerebroventricularly applied nociceptin, measured in the mouse tail withdrawal assay. Moreover, [Nphe 1 ]nociceptin(1‐13)NH 2 produces per se a dose dependent, naloxone resistant antinociceptive action and, at relatively low doses, potentiates morphine‐induced analgesia. Collectively our data indicate that [Nphe 1 ]nociceptin(1‐13)NH 2 , acting as a nociceptin receptor antagonist, may be the prototype of a new class of analgesics.British Journal of Pharmacology (2000) 129 , 1183–1193; doi: 10.1038/sj.bjp.0703169