Characterization of [Nphe1]nociceptin(1‐13)NH2, 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 pept...

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Bibliographic Details
Published in:British journal of pharmacology 2000-03, Vol.129 (6), p.1183-1193
Main Authors: Calo', Girolamo, Guerrini, Remo, Bigoni, Raffaella, Rizzi, Anna, Marzola, Giuliano, Okawa, Hirobumi, Bianchi, Clementina, Lambert, David G, Salvadori, Severo, Regoli, Domenico
Format: Article
Language:English
Subjects:
[Nphe1]nociceptin(1‐13)NH2
Analgesics
Biological and medical sciences
isolated tissues
Medical sciences
morphine, analgesia
mouse tail withdrawal assay
native and recombinant receptors
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Nociceptin
nociceptin receptor antagonist
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
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Summary: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 [Nphe1]nociceptin(1‐13)NH2 acts as the first truly selective and competitive nociceptin receptor antagonist and is devoid of any residual agonist activity. [Nphe1]nociceptin(1‐13)NH2 binds selectively to recombinant nociceptin receptors expressed in Chinese hamster ovary (CHO) cells (pKi 8.4) and competitively antagonizes the inhibitory effects of nociceptin (i) on cyclic AMP accumulation in CHO cells (pA2 6.0) and (ii) on electrically evoked contractions in isolated tissues of the mouse, rat and guinea‐pig with pA2 values ranging from 6.0 to 6.4. [Nphe1]nociceptin(1‐13)NH2 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, [Nphe1]nociceptin(1‐13)NH2 produces per se a dose dependent, naloxone resistant antinociceptive action and, at relatively low doses, potentiates morphine‐induced analgesia. Collectively our data indicate that [Nphe1]nociceptin(1‐13)NH2, 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
ISSN:0007-1188
1476-5381
DOI:10.1038/sj.bjp.0703169