Disease relevance of PNOC

• The results demonstrate that N/OFQ can effectively stimulate MAPK by the activation of ORL1 receptor and pertussis toxin-sensitive G proteins, and that phospholipase C, as well as protein kinase C, is critically involved in these processes [1].
• Mu-Opioid receptors have been shown to contribute to orphanin FQ/nociceptin (OFQ/N)-mediated analgesia and hyperalgesia, indicating that both pro- and antinociceptive actions of OFQ/N are influenced by mu-opioid receptors [2].
• The present data demonstrated that astrocyte activation and enhanced cytokine expression at the CNS had a role in eliciting behavioral hypersensitivity; the anti-nociception function of N/OFQ might be dependent on cytokines derived from astrocytes, the effects were attributable to the ORL1 receptor pathway [3].
• This study was designed to investigate the intracellular signaling mechanism of N/OFQ in human dopaminergic neuroblastoma SH-SY5Y cells [4].
• The effect occurs at doses that are not hyperphagic per se and is clearly selective versus the anorectic action of CRF since N/OFQ or Ro 64-6198 do not influence the anorectic effect of Escherichia coli lipopolysaccharide (LPS) [5].

Psychiatry related information on PNOC

• 4. UFP-101 is also active in vivo where it prevented the depressant action on locomotor activity and the pronociceptive effect induced by 1 nmol N/OFQ i.c.v. in the mouse [6].
• Many studies point toward the nociceptin/orphanin FQ (N/OFQ) and the N/OFQ peptide receptor (NOP) as targets for the development of innovative drugs for treating affective disorders [7].
• Together, these findings suggest that N/OFQ and its receptor may represent an interesting target for pharmacological treatment of alcohol abuse [8].
• Other possible applications of OFQ/N agonists and antagonists include treatment of depression, anorexia and rewarding aspects of drug addiction [9].
• Also, data suggest that N/OFQ may not only promote feeding initiation, but rather its role may be to inhibit signaling responsible for inhibition of consummatory behavior [10].

High impact information on PNOC

• This review will address the molecular biology and behavioral pharmacology of OFQ/N and its receptor [11].
• The number and diversity of papers focused on OFQ/N1-17 at the recent meeting of the Society for Neuroscience augur an exciting future for this new peptide [12].
• The predicted amino acid sequence of the OFQ precursor contains a putative signal peptide and one copy of the OFQ sequence flanked by pairs of basic amino acid residues [13].
• Alanine- and D-amino acid-scanning mutagenesis revealed several residues in the amino-terminal half of OFQ which participate in both receptor binding and activation [14].
• In addition, in cells expressing mu receptors in which the GRK-mediated phosphorylation site Ser(375) was mutated to alanine, OFQ/N treatment failed to potentiate DAMGO-induced mu receptor phosphorylation and failed to desensitize the mu receptor [15].

Chemical compound and disease context of PNOC

• For example, in the ventromedial nucleus of the hypothalamus (VMH), OFQ/N facilitates lordosis in female rats through estrogen and progesterone regulation of nociceptin activity [16].
• Nocistatin also attenuated the allodynia and hyperalgesia evoked by prostaglandin E(2) and the inflammatory hyperalgesia induced by formalin or carrageenan/kaolin, and reversed the Noc/OFQ-induced inhibition of morphine analgesia at picogram doses [17].

Biological context of PNOC

• Agonistic effect of buprenorphine in a nociceptin/OFQ receptor-triggered reporter gene assay [18].
• N/OFQ and N/OFQ(1-13)NH(2) inhibited the forskolin-induced luciferase gene expression with IC(50) values of 0.81 +/- 0.5 and 0.87 +/- 0.16 nM, respectively [18].
• Previous studies have reported alternative splicing between exons 3 and 4 of the mouse OFQ/N transcript, which, upon translation, would yield precursor proteins with different C-termini [19].
• When human embryonic kidney 293 cells stably expressing the human ORL1 receptor were pre-exposed (30 min) to either OFQ/N or Ro 64-6198, the ability of both agonists to inhibit forskolin-mediated cAMP accumulation was strongly reduced, indicating a functional desensitization of the second messenger cascade [20].
• Interestingly, KT5720, a specific inhibitor of PKA, markedly suppressed the phosphorylation of MAPK by N/OFQ in SH-SY5Y cells [4].

Anatomical context of PNOC

• In CHO cells, 125I-Tyr14-OFQ detected a single affinity state with an intermediate Kd value of 54 pM [21].
• In rat brain membranes, specific, saturable binding of 125I-Tyr14-OFQ was demonstrated to be pharmacologically identical to the heterologously expressed OFQ-R [21].
• The Spiegelmers antagonized the N/OFQ-induced GTPgammaS incorporation into cell membranes of a CHO-K1 cell line expressing the human ORL1 receptor [22].
• When the ORL1 receptor was transiently co-expressed in COS-7 cells with the alpha-subunit of G16, nociceptin/OFQ dose-dependently stimulated the formation of inositol phosphates [23].
• In the present study, we investigated: (1) astrocyte activation and proinflammatory cytokine expression at the lumbar spinal cord following intraplantar administration of complete Freund's adjuvant (CFA) in rats; (2) the mechanism of N/OFQ on nociception modulation, the relationship between N/OFQ and cytokines in the rat CNS in vivo and in vitro [3].

Associations of PNOC with chemical compounds

• In cells expressing both ORL-1 (OFQR) and mu-opioid receptors, pretreatment with nociceptin decreased subsequent nociceptin (OFQ)- or DAMGO-stimulated MAP kinase activation [24].
• In HEK 293 cells transiently expressing the ORL1 and dopamine D1 receptors, nociceptin/OFQ dose-dependently inhibited dopamine-stimulated cyclic AMP (cAMP) accumulation in a PTX-sensitive manner [23].
• However, PTX failed to block the nociceptin/OFQ-induced inhibition of dopamine-stimulated cAMP accumulation in HEK 293 cells co-expressing the alpha-subunit of Gz [23].
• U-73122, a phospholipase C-specific inhibitor, significantly inhibited phospholipase C activity, as well as MAPK activation stimulated by N/OFQ [1].
• Further, (+)-5a potently stimulated GTP gamma S binding to NOP membranes (EC50 = 65 nM) and inhibited forskolin-mediated cAMP accumulation in NOP-expressing cells (EC50 = 9.1 nM) with a potency comparable to that of the natural peptide agonist N/OFQ [25].

Physical interactions of PNOC

• These compounds were tested for binding affinity using [3H]N/OFQ binding to human ORL1 in CHO cells, and functional activity by measuring stimulation of [35S]GTPgammaS binding in CHO cell membranes [26].

Regulatory relationships of PNOC

• Our results demonstrate for the first time the involvement of conventional PKC isozymes in OFQ/N-induced mu-ORL1 cross-talk, and represent a possible mechanism for OFQ/N-induced anti-opioid actions [27].
• However, on re-stimulated T cells N/OFQ causes inhibition of proliferation, which could be linked with N/OFQ up-regulating CTLA-4 expression [28].
• Inclusion of OFQ/N during chronic morphine exposure also blocked morphine-induced TH upregulation [29].
• Taken together, these results suggest that N/OFQ independently induces the activation of CREB prior to MAPK phosphorylation, which was also modulated by PKA [4].

Other interactions of PNOC

• Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the opioid receptor-like receptor or nociceptin receptor (NOP) [30].
• This study shows that N/OFQ (10(-14)-10(-12) M) modulates T cell activation by up-regulating activation marker expression, e.g. CD28, leading to enhanced proliferation and modulation of TNFalpha secretion [28].
• Pretreatment with orphanin FQ/nociceptin (OFQ/N) also upregulated GRK3 levels in both cell lines, and desensitized both receptors in BE(2)-C cells [31].
• Here, we demonstrate for the first time a role for ERK1/2-mediated GRK2 induction in the development of tolerance to mu agonists, as well as cross-tolerance to OFQ/N [31].
• Furthermore, chronic OFQ/N exposure increased levels of the TH gene repressor, Oct-2, irrespective of the presence or absence of morphine [29].

Analytical, diagnostic and therapeutic context of PNOC

• In situ hybridization of rat brain slices demonstrated a regional distribution pattern of the OFQ precursor mRNA, which is distinct from that of the opioid peptide precursors [13].
• A physiologic role for nociceptin (OFQ) activation of the ORL-1 receptor (OFQR) may be to modulate opioid-induced analgesia [24].
• We measured the concentrations of N/OFQ in 47 microdissected areas of the central nervous system of adult human brain using radioimmunoassay (RIA) [32].
• The receptor mRNA is likely to arise from a single gene, as determined by Southern blotting of porcine genomic DNA restriction digests using a porcine OFQ receptor cDNA probe [33].
• In contrast, the blockade of N/OFQ signaling obtained with NOP-selective antagonists promotes antidepressant-like effects in the forced swimming and tail suspension tests [7].

References