Nociceptin/Orphanin FQ Peptide Receptors: Pharmacology and Clinical Implications

Abstract

The advance of functional genomics revealed the superfamily of G-protein coupled receptors (GPCRs). Hundreds of GPCRs have been cloned but many of them are orphan GPCRs with unidentified ligands. The first identified orphan GPCR is the opioid receptor like orphan receptor, ORL1. It was cloned in 1994 during the identification of opioid receptor subtypes and was de-orphanized in 1995 by the discovery of its endogenous ligand, nociceptin or orphanin FQ (N/OFQ). This receptor was renamed as N/OFQ peptide (NOP) receptor. Several selective ligands acting at NOP receptors or other anti-N/OFQ agents have been reported. These include N/OFQ-derived peptides acting as agonists (cyclo[Cys(10),Cys(14)]N/OFQ, [Arg(14), Lys(15)]N/OFQ, [pX]Phe(4)N/OFQ(1-13)-NH(2), UFP-102, [(pF)Phe(4),Aib(7), Aib(11),Arg(14),Lys(15)]N/OFQ-NH(2)) or antagonists (Phe(1)psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)-NH(2), [Nphe(1)]N/OFQ(1-13)-NH(2), UFP-101, [Nphe(1), (pF)Phe(4),Aib(7),Aib(11),Arg(14),Lys(15)]N/OFQ-NH(2)), hexapeptides, other peptide derivatives (peptide III-BTD, ZP-120, OS-461, OS-462, OS-500), non-peptide agonists (NNC 63-0532, Ro 64-6198, (+)-5a compound, W-212393, 3-(4-piperidinyl)indoles, 3-(4-piperidinyl) pyrrolo[2,3-b]pyridines) and antagonists (TRK-820, J-113397, JTC-801, octahydrobenzimidazol-2-ones, 2-(1,2,4-oxadiazol-5-yl)-1 H-indole, N-benzyl-D-prolines, SB-612111), biostable RNA Spiegelmers specific against N/OFQ, and a functional antagonist, nocistatin. Buprenorphine and naloxone benzoylhydrazone are two opioid receptor ligands showing high affinity for NOP receptors. NOP receptor agonists might be beneficial in the treatment of pain, anxiety, stress-induced anorexia, cough, neurogenic bladder, edema, drug dependence, and, less promising, in cerebral ischemia and epilepsy, while antagonists might be of help in the management of pain, depression, dementia and Parkinsonism. N/OFQ is also involved in cardiovascular, gastrointestinal and immune regulation. Altered plasma levels of N/OFQ have been reported in patients with various pain states, depression and liver diseases. This review summarizes the pharmacological characteristics of, and studies with, the available NOP receptor ligands and their possible clinical implications.

Nociceptin/orphanin FQ receptor blockade attenuates MPTP-induced parkinsonism

“…Although the inconsistency of response prevents from drawing firm conclusions on the role of endogenous N/OFQ, the data obtained in two animals are in line with the view that the peptide plays an inhibitory role on motor activity. Nevertheless, high doses of J-113397 may also activate sigma receptors (Chiou et al, 2007), causing loss of attention and hallucinations (Okuyama et al, 1994).…”

Nociceptin Receptor Impairs Recognition Memory via Interaction with NMDA Receptor-Dependent Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling in the Hippocampus

“…Since its discovery a decade ago, this neuropeptidereceptor system has been implicated in a host of biological functions (Chiou et al, 2007). One of the most established findings is the importance of this system in cognition.…”

In-vivo effects of nociceptin and its structural analogue [Orn9] nociceptin on the antioxidant status of rat blood and liver after carrageenan-induced paw inflammation

“…Although there are differences in the peptide precursor, the sequence of this heptadecapeptide is the same in mouse, rat, and human; for details see the review of Calo et al [1]. On the basis of pharmacological and physiological characteristics, NOP receptor ligands (agonists and antagonists) could be useful for treatment of pain, anxiety, depression, dementia, parkinsonism, stress-induced anorexia, neurogenic bladder, oedema, or drug dependence [2].…”

“…Using the CG model, we tested the effects of N/OFQ(1-13)NH 2 and its structural analogue [Orn 9 ]N/OFQ(1-13)NH 2 on the antioxidant status of red blood cells and liver. Four hours after CG injection, the volume and the tissue mass of the inflamed paw increased, i.e., a local paw inflammation was achieved.…”