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  • Review Article
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The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential

Nature Reviews Drug Discovery volume 7, pages 694–710 (2008)Cite this article

Key Points

  • Nociceptin/orphanin FQ (N/OFQ) is the first example of a peptide that was isolated by reverse pharmacology.

  • N/OFQ activates a Gi-protein-coupled receptor, NOP, and this peptide–receptor system has been implicated in a diverse range of biological functions including (but not limited to) pain, reward/drug abuse, cardiovascular control and immune function.

  • Many peptide and non-peptide ligands are available. The main chemical classes of the current non-peptides are morphinans (for example, buprenorphine; mixed); aminoquinolines (for example, JTC-801; antagonist); benzimidazopiperidines (for example, J-113397; antagonist); aryl-piperidines (for example, SB-612111; antagonist); and spiropiperidines (for example, Ro64-6198; agonist).

  • Central NOP antagonists have, variably, antinociceptive (supraspinal), and antidepressant effects. Central NOP agonists have anti-opioid (supraspinal), antinociceptive (spinal), anxiolytic effects and produce bradycardia/hypotension.

  • Peripheral NOP agonists have antinociceptive, vasodilatory and aquaretic effects. They also produce bardycardia and hypotension, and inhibit bladder activity.

  • A small number of molecules are in clinical development: ZP120, a peptide in Phase I and II for congestive heart failure, and JTC-801, a non-peptide antagonist in Phase II for pain.

Abstract

Identification of the enigmatic nociceptin/orphanin FQ peptide (N/OFQ) in 1995 represented the first successful use of reverse pharmacology and led to deorphanization of the N/OFQ receptor (NOP). Subsequently, the N/OFQ–NOP system has been implicated in a wide range of biological functions, including pain, drug abuse, cardiovascular control and immunity. Although this could be considered a hurdle for the development of pharmaceuticals selective for a specific disease indication, NOP represents a viable drug target. This article describes potential clinical indications and highlights the current status of the very limited number of clinical trials.

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Figure 1: Pleiotropic effects of nociceptin/orphanin FQ (N/OFQ) on major organ systems.
Figure 2: Non-peptide nociceptin/orphanin FQ receptor (NOP) ligands.
Figure 3: Schematic to describe the interrelationship between the anatomical site(s) underlying the actions of N/OFQ on pain.
Figure 4: Involvement of N/OFQ–NOP in depression and anxiety: NOP antagonists are antidepressant and agonists are anxiolytic.

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Acknowledgements

I am indebted to my collaborators G. Calo and R. Guerrini (University of Ferrara, Italy) for advice in the construction of this Review and for critically reading several versions. I would also like to thank R. Ciccocioppo, Department of Pharmacological Sciences and Experimental Medicine, University of Camerino, Italy, for advice on the reward/abuse section and J. McDonald for help in manuscript preparation. Over the years work on N/OFQ in my laboratory has been funded by the British Journal of Anaesthesia and the Royal College of Anaesthetists, The Wellcome Trust and Pfizer (Sandwich, UK). A PubMed search for “nociceptin” or “orphanin” yields ∼1,300 hits, so I apologize to all those authors whose work I could not cite due to limitations of space.

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  1. Department of Cardiovascular Sciences (Pharmacology and Therapeutics Group), Division of Anaesthesia, Critical Care and Pain Management, University of Leicester, Leicester Royal Infirmary, Leicester, LE1 5WW, UK

    David G. Lambert

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Supplementary information

Supplementary information S1 (table)

Opioid receptor classification (IUPHAR), transduction and basic pharmacology. (PDF 166 kb)

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FURTHER INFORMATION

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IUPHAR Receptor Database

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Glossary

Hyperalgesia

An increase in pain perception above the normal response to a stimulus.

Deorphanized

The identification of an endogenous ligand for a receptor whose structure makes it a member of a receptor family, but for which no ligand has yet been identified (that is, an orphan receptor).

Structure–activity relationship

(SAR). Correlations that are constructed between the features of chemical structure in a set of candidate compounds and parameters of biological activity, such as potency, selectivity and toxicity.

Superagonist

A drug that can interact with a receptor and initiate a physiological or a pharmacological response that is characteristic of that receptor but with particularly high potency and/or efficacy.

Privileged structure

A single molecular framework that is able to provide ligands for diverse receptors.

Conditioned place preference (CPP) test

An experimental animal is presented with a positive stimulus (in this case a drug of abuse) in conjunction with a specific cue. The animal develops an association between the place and preference for the positive stimulus. The amount of time spent in the place previously associated with the stimulus can be used as an index of the rewarding properties of the original stimulus.

Marchigian Sardinian alcohol-preferring (mSP) rat

A genetically selected strain of rat with a natural preference for ethanol. This is used as a model of human alcoholism.

GTPγ [35S] binding

An in vitro assay used to monitor G-protein coupled receptor-mediated guanine nucleotide exchange at G proteins.

Sympatholytic

An agent that decreases the activity of the sympathetic nervous system, for example, guanethidine.

Chronotropic effect

In the context of the cardiovascular system, this refers to heart rate. Opioids slow heart rate and thus have a negative chronotropic effect.

Hyponatraemia

Low plasma sodium concentration.

Capsaicin-sensitive primary afferents

These are primary nociceptive afferent fibres of the Aδ and C-fibre type. They express TRPV1 receptors and hence are capsaicin sensitive. As TRPV1 receptors are also activated by heat and low pH, these channels convey a polymodal activation profile to Aδ and C-fibres.

Detrusor hyperreflexia

Increased contractility of the detrusor muscle of the bladder (idiopathic), often as a result of neurological disease (neurogenic), leading to urinary incontinence.

Afferent fibre switching

Afferent signals from the bladder are conveyed by Aδ and C-fibres, with the latter being 'silent'. In spinal-cord injury, C-fibre activity is unmasked, leading to fibre switching.

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Lambert, D. The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential. Nat Rev Drug Discov 7, 694–710 (2008). https://doi.org/10.1038/nrd2572

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