The nociceptin (ORL1) receptor: molecular cloning and functional architecture

doi:10.1016/S0196-9781(00)00225-4

Peptides

Volume 21, Issue 7, July 2000, Pages 893-900

https://doi.org/10.1016/S0196-9781(00)00225-4 Get rights and content

Abstract

Nociceptin and the ORL1 receptor share high sequence similarity with opioid peptides, particularly dynorphin A, and their receptors. However, nociceptin and dynorphin A may use distinct molecular pathways to bind and activate their cognate receptors. Activation of the κ-opioid receptor by dynorphin A is thought to require interactions of its N-terminal hydrophobic domain (Y¹GGF) with the receptor opioid binding pocket, located within the transmembrane helix bundle, while activation of the ORL1 receptor appears to require interactions of the positively charged core (R⁸KSARK) of nociceptin with the negatively charged second extracellular receptor loop.

Introduction

Pharmacological studies have firmly established that there are three major types, δ, μ, and κ, of opioid receptor. Molecular cloning of the δ-opioid receptor [15], [26] was soon followed by the cloning of the μ- and κ-opioid receptors [27]. Further attempts to clone additional opioid receptor types and/or subtypes, by hybridization screening at low stringency with opioid receptor cDNA probes, or using probes generated by selective amplification of genomic DNA with degenerate primers [34], led several laboratories to isolate a cDNA encoding a homologous protein with a high degree of sequence similarity to the opioid receptors. This previously unrecognized receptor did not, however, bind opiates and opioid receptor antagonists with high affinity. The receptor remained “orphan” until late 1995, when two groups independently reported the isolation, from brain extracts, of its endogenous ligand, nociceptin [42], or orphanin FQ [54], a new member of the endorphin family [25]. In addition to providing a clear cut example of the successful application of reverse pharmacology [41], [60], the discovery of nociceptin “marked the sprouting of a new area in brain research” [55]. Indeed, a considerable body of information concerning all aspects of the novel neuropeptide has already accumulated. Although nociceptin acts at the molecular and cellular level in very much the same way as opioids do, it can produce pharmacological effects that sometimes differ from, and even oppose, those of opioids [11], [21], [40]. Most importantly, the broad pharmacological profile of nociceptin points to a number of potential therapeutic applications, especially those associated with pain, stress and anxiety, eating disorders, cognitive deficiency, drug addiction, motor coordination disabilities, hypertension, masculine impotence, and water retention.

The discovery of the nociceptin peptide is likely to prompt the development of novel non-peptidic ORL1 receptor ligands, agonists and antagonists, that are both proteinase resistant, and not subject to problems of bioavailability. Lead compounds may be identified in natural (i.e. animal or plant) extracts, extant pharmaceutical drug repositories (such as lofentanil; ref. 6), or synthetic combinatorial libraries (such as the Houghten peptides; ref. 14), using conventional drug screening techniques. Alternatively, they may be rationally designed, on the basis of a reliable structure of the ORL1 receptor and its complex with nociceptin.

Section snippets

The ORL1 receptor gene and product(s)

The ORL1 receptor was first cloned as an orphan opioid receptor-like receptor from human [45], rat [5], [9], [18], [30], [49], [65], and mouse [47] brain, and human lymphocytes [20], [67].

Alignment of the cDNA-deduced amino acid sequences of the human ORL1, δ-, μ-, and κ-opioid receptors reveals conserved regions, notably in the transmembrane helices and cytoplasmic loops (Fig. 1). The statistics (see Table 1 ) show that sequence conservation among the four receptors is highest (>70%) in the

The ORL1 receptor endogenous ligand, nociceptin/orphanin FQ

Implementation of a reverse pharmacology (functional genomics) approach, based upon the ORL1 receptor-mediated adenyl cyclase inhibition assay in recombinant CHO cells [45], led to the isolation and identification of the heptadecapeptide nociceptin/orphanin FQ as the endogenous ligand of the orphan receptor [42], [54]. As might have been anticipated from the structural homology of the ORL1 and κ-opioid receptors (see above), nociceptin bears a clear resemblance to dynorphin A, also a

How does nociceptin bind and activate the ORL1 receptor?

Nociceptin binds the ORL1 receptor with a 500- to 1000-fold higher affinity than it does the κ-opioid receptor. Conversely, dynorphin A binds the κ-opioid receptor 500- to 1000-fold tighter than the ORL1 receptor. Likewise, nociceptin is a potent agonist of the ORL1 receptor, but is inactive toward the κ-opioid receptor. Dynorphin A is a potent agonist of the κ-opioid receptor and inactive at the ORL1 receptor. Thus, the structural homology of the receptors and the similar physical and chemical

Conclusions

Although the ORL1 and κ-opioid receptors share high sequence similarity, and nociceptin and dynorphin A possess common physical and chemical characteristics, distinct peptide–receptor interactions appear to be required for the recognition and activation of the two receptors by their cognate peptides. Activation of the ORL1 receptor by nociceptin is proposed to require interactions of the positively charged peptide core with the negatively charged second extracellular receptor loop. Activation

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The Nociceptin/Orphanin FQ (N/OFQ) system has been shown to modulate various aspects of long-term memory. It is therefore important to study the effects on memory impairment by nociceptin receptor (NOP) agonists under preclinical development. In the present study, we investigated the effect of systemic injection of two small molecule selective NOP agonists, AT-202 and AT-524, in the object location memory task in male and female mice. Since high doses of NOP agonists have been shown to induce sedation, we first determined the sedative doses for the two compounds and found them to be higher in female than in male mice. We then observed that sub-sedative doses of NOP agonists administered before learning, induced memory impairment during a test session performed 24 h later. Again, female mice were less sensitive to the amnesic effects than males. On the contrary, in male mice, NOP agonists did not produce amnesia when they were injected after learning, suggesting that they do not affect the consolidation of object location memory. Finally, repeated administration of high doses of NOP agonists over 7 days did not impair long-term spatial memory. Together, our data show for the first time that NOP receptor agonists impair the acquisition of object location memory with sex-dependent potency but do not affect memory consolidation, and that repeated stimulation of the receptor does not compromise long-term episodic-like spatial memory.
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In agreement with this notion, we also proved that cORL1 could be specifically activated by nociceptin. It is generally believed that Phe1 of nociceptin contributed to its specificity in binding ORL1 in mammals [56]. However, chicken nociceptin used Tyr1 as its leading amino acid at the N-terminus.
Opioid peptides, derived from PENK, POMC, PDYN and PNOC precursors, together with their receptors (DOR, MOR, KOR and ORL1), constitute the opioid system and are suggested to participate in multiple physiological/pathological processes in vertebrates. However, the question whether an opioid system exists and functions in non-mammalian vertebrates including birds remains largely unknown. Here, we cloned genes encoding opioid system from the chicken brain and examined their functionality and tissue expression. As in mammals, 6 opioid peptides encoded by PENK (Met-enkephalin and Leu-enkephalin), POMC (β-endorphin), PDYN (dynorphin-A and dynorphin-B) and PNOC (nociceptin) precursors and four opioid receptors were found to be highly conserved in chickens. Using pGL3-CRE-luciferase and pGL4-SRE-luciferase reporter systems, we demonstrated that chicken opioid receptors (cDOR, cMOR, cKOR and cORL1) expressed in CHO cells, could be differentially activated by chicken opioid peptides, and resulted in the inhibition of cAMP/PKA and activation of MAPK/ERK signaling pathways. cDOR is potently activated by Met-enkephalin and Leu-enkephalin, and cKOR is potently activated by dynorphin-A, dynorphin-B and nociceptin, whereas cORL1 is specifically activated by nociceptin. Unlike cDOR, cKOR and cORL1, cMOR is moderately/weakly activated by enkephalins and other opioid peptides. These findings suggest the ligand-receptor pair in chicken opioid system is similar, but not identical to, that in mammals. Quantitative real-time PCR revealed that the opioid system is mainly expressed in chicken central nervous system including the hypothalamus. Collectively, our data will help to facilitate the better understanding of the conserved roles of opioid system across vertebrates.
Activation of nociceptin/orphanin FQ receptors inhibits contextual fear memory reconsolidation
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Nociceptin/orphanin FQ (N/OFQ) is a 17-amino acid neuropeptide related to the opioid family (Meunier et al., 1995; Reinscheid et al., 1995). However it does not interact with classical mu, delta and kappa opioid receptors but with another opioid-like G-protein-coupled receptor called ORL1 or NOP (Meunier et al., 2000). Consistent with its widespread distribution in the central nervous system N/OFQ has been shown to modulate many physiological functions in rodents such as pain, feeding, cardiovascular control, reward, stress/anxiety and depression-like behavior (Calo et al., 2000; Lambert, 2008; Zaveri, 2016).
Several neuropeptidergic systems act as modulators of cognitive performances. Among them, nociceptin, an opioid-like peptide also known as orphanin FQ (N/OFQ), has recently gained attention. Stimulation of its receptor, the N/OFQ opioid receptor (NOP), which is expressed in brain regions involved in emotion, memory and stress response, has inhibitory effects on the acquisition and/or consolidation of spatial and emotional memory in rodents. Recently, N/OFQ was also proposed to be linked to the pathogenesis of Post-Traumatic Stress Disorder in humans. However, until now the effect of the activation of the N/OFQ-NOP system on already consolidated memory, such as during retrieval and reconsolidation phases, has never been explored. In the present study, we investigated the consequences of systemic injection of NOP agonists or i.c.v. injection of the N/OFQ peptide on the retrieval and the reconsolidation of contextual fear memory in mice. We demonstrate that the activation of the N/OFQ system impairs the reconsolidation of context-dependent but not cue-dependent aversive memories. We also show that this amnestic effect is associated with decreased c-Fos expression in the hippocampus and amygdala. Our data thus provide the first evidence that the NOP receptor could be targeted during the reconsolidation process to weaken maladaptive memories. The N/OFQ-NOP system might constitute in the future an interesting pharmacological target for interfering with so-called “pathological memories”, in particular those involving maladaptive contextual memories.
Migraine and neuropeptides
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The NOP1 receptor is widely distributed in the CNS, e.g. in the hypothalamus, the brainstem and the dorsal horn of the spinal cord (Bridge et al., 2003; Mollereau and Mouledous, 2000). NOP has multidirectional effects in the CNS, exerting algesic, hyperalgesic and analgesic properties, while in the PNS it displays antinociceptive effects (Ertsey et al., 2005; Giuliani et al., 2000; Meunier et al., 2000; Reinscheid et al., 2000). In tracing experiments with immunohistochemical visualization, NOP-ir fibres of trigeminal origin were detected in the dorsal horn of the cervical spinal cord (Marfurt and Del Toro, 1987).
Migraine is a common disabling neurovascular primary headache disorder. The pathomechanism is not clear, but extensive preclinical and clinical studies are ongoing. The structural basis of the leading hypothesis is the trigeminovascular system, which includes the trigeminal ganglion, the meningeal vasculature, and the distinct nuclei of the brainstem, the thalamus and the somatosensory cortex. This review covers the effects of sensory (calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide and substance P), sympathetic (neuropeptide Y) and parasympathetic (vasoactive intestinal peptide) migraine-related neuropeptides and the functions of somatostatin, nociceptin and the orexins in the trigeminovascular system. These neuropeptides may take part in neurogenic inflammation (plasma protein extravasation and vasodilatation) of the intracranial vasculature and peripheral and central sensitization of the trigeminal system. The results of human clinical studies are discussed with regard to the alterations in these neuropeptides in the plasma, saliva and cerebrospinal fluid during or between migraine attacks, and the therapeutic possibilities involving migraine-related neuropeptides in the acute and prophylactic treatment of migraine headache are surveyed.
The role of nociceptin and dynorphin in chronic pain: Implications of neuro-glial interaction
2011, Neuropeptides
Citation Excerpt :
The NOC and DYN systems share many similarities in structure and in their distributions within the CNS and PNS despite belonging to distinct neuropeptide groups. DYN belongs to the classical opioid system, whereas NOC acts similarly to traditional opioids, as it produces membrane hyperpolarization through the opening of potassium channels (Connor et al., 1996; Vaughan and Christie, 1996); however, in contrast to opioids (e.g., DYN), NOC does not act on any classical opioid receptors because of its lack of an N-terminal tyrosine (Meunier et al., 2000; Nothacker et al., 1996; Reinscheid et al., 1995). NOC (Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln), which was previously known as orphanin FQ (OFQ; Reinscheid et al., 1998), is produced from the precursor pronociceptin (PNOC; Boom et al., 1999; Houtani et al., 1996; Lapalu et al., 1997; Meunier et al., 1995) and is an endogenous ligand of the nociceptin-opioid peptide (NOP) receptor, which was previously known as opioid receptor like-1 (ORL1).
Nociceptin-opioid peptide (NOP) receptor, also known as opioid receptor like-1 (ORL1), was identified following the cloning of the kappa-opioid peptide (KOP) receptor, and the characterization of these receptors revealed high homology. The endogenous ligand of NOP, nociceptin (NOC), which shares high homology to dynorphin (DYN), was discovered shortly thereafter, and since then, it has been the subject of several investigations. Despite the many advances in our understanding of the involvement of NOC and DYN systems in pain, tolerance and withdrawal, the precise function of these systems has not been fully characterized. Here, we review the recent literature concerning the distribution of the NOC and DYN systems in the central nervous system and the involvement of these systems in nociceptive transmission, especially under chronic pain conditions. We discuss the use of endogenous and exogenous ligands of NOP and KOP receptors in pain perception, as well as the potential utility of NOP ligands in clinical practice for pain management. We also discuss the modulation of opioid effects by NOC and DYN. We emphasize the important role of neuro–glial interactions in the effects of NOC and DYN, focusing on their presence in neuronal and non-neuronal cells and the changes associated with chronic pain conditions. We also present the dynamics of immune and glial regulation of neuronal functions and the importance of this regulation in the roles of NOC and DYN under conditions of neuropathic pain and in the use of drugs that alter these systems for better control of neuropathic pain.
Bradycardia elicited by microinjections of nociceptin/orphanin FQ into the intermediolateral cell column at T1-T2 in the rat
2007, Neuroscience Letters
Microinjections (30 nl) of nociceptin/orphanin FQ (N/OFQ) into the intermediolateral cell column (IML) at T1 and T2 levels of the spinal cord elicited bradycardia. The decreases in HR were 12.3 ± 2.9, 17.3 ± 2.7, 26.7 ± 3.1, and 18.6 ± 3.4 beats/min in response to 0.075, 0.15, 0.62, and 1.25 mM concentrations, respectively. Maximally effective concentration of N/OFQ was 0.62 mM. No changes in BP were elicited by microinjections of N/OFQ into the IML at T1–T2. The bradycardic responses were completely blocked by prior microinjections of a N/OFQ receptor (NOP receptor) antagonist ([N-phe¹]-nociceptin-(1-13)-NH₂, 9 mM) into the IML at T1–T2. Blockade of myocardial β-1 adrenergic receptors also abolished the bradycardic responses elicited by microinjections of N/OFQ into the IML. It was concluded that activation of NOP receptors in right IML at T1–T2 by N/OFQ elicited bradycardic responses which were mediated via the sympathetic nervous system.

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^☆: Financial support was received from the Association pour la Recherche sur le Cancer (ARC # 9428), and the European Commission (Biomed 2 Programme # BMH4-CT97–2317).

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Regular paperThe nociceptin (ORL1) receptor: molecular cloning and functional architecture☆

Abstract

Introduction

Section snippets

The ORL1 receptor gene and product(s)

The ORL1 receptor endogenous ligand, nociceptin/orphanin FQ

How does nociceptin bind and activate the ORL1 receptor?

Conclusions

J Mol Biol

J Biol Chem

FEBS Lett

Eur J Pharmacol

FEBS Lett

Trends Neurosci

J Mol Graphics

Biochim Biophys Acta

cDNA cloning and regional distribution of a novel member of the opioid receptor family. FEBS Lett

J Neuroimmunol

Trends Pharmacol Sci

J Mol Biol

J Mol Biol

FEBS Lett

FEBS Lett

FEBS Lett

Brain Res

Biochem Biophys Res Commun

J Biol Chem

Eur J Pharmacol

FEBS Lett

FEBS Lett

Biochem Biophys Res Commun

J Biol Chem

Biophys J

J Biol Chem

J Biol Chem

Lancet

Biochem Biophys Res Commun

J Biol Chem

Trends Pharmacol Sci

J Biol Chem

FEBS Lett

5]decan-4-one derivatives as orphanin FQ receptor agonists. Bioorg Med Chem Lett

Regular paper
The nociceptin (ORL1) receptor: molecular cloning and functional architecture☆