Ligands Raise the Constraint That Limits Constitutive Activation in G Protein-coupled Opioid Receptors

Vezzi, Vanessa; Onaran, Hilal; Molinari, Paola; Guerrini, Remo; Balboni, Gianfranco; Calò, Girolamo; Costa, Tommaso

doi:10.1074/jbc.m113.474452

Cited by 20 publications

(25 citation statements)

References 34 publications

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“…Very recently using a BRET-based assay to investigate NOP receptor/G-protein interactions, it was demonstrated that GDP was not able to significantly inhibit the baseline BRET ratio (Malfacini et al, 2015). However, in membranes expressing the other opioid receptors, under similar experimental conditions, GDP can suppress the baseline BRET ratio, indicating a reduction in spontaneous receptor/G-protein interactions, with maximal effects 4-5 times greater at delta than mu receptors (Vezzi et al, 2013). Thus these results demonstrate that the propensity to display constitutive activity is much lower for NOP compared with the mu and particularly the delta opioid receptor.…”

Section: A Nociceptin Opioid Peptide Receptor Proteinmentioning

confidence: 99%

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

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The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor

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Section: A Nociceptin Opioid Peptide Receptor Proteinmentioning

confidence: 99%

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

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“…On the other hand, cellular mechanisms may warrant high concentrations of signaling partners in physiologic conditions and, at the same time, mass action is most likely only one of many factors influencing DOPr association into multimeric arrays. For example, although the spontaneous transfer of energy between BRET pairs consisting of DOPr and Gb1 subunits was susceptible to modulation by guanine nucleotides, the interaction between overexpressed MOPrs and Gb1 was not (Molinari et al, 2010), arguing that high constitutive activity and not only mass action may have contributed to the spontaneous association between DOPr and G proteins (Costa and Herz, 1989;Vezzi et al, 2013).…”

Section: D-opioid Receptor Pharmacologymentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

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“…Second, the increase in constitutively active MORs could be a result of a change in the intrinsic energy constraint that limits constitutive activity (Vezzi et al, 2013). This new model is an extension to the extended ternary complex model (De Léan et al, 1980;Wreggett and De Léan, 1984;Weiss et al, 1996) and proposes that an intrinsic, intramolecular energy constraint limits constitutive activity.…”

Section: Mechanisms For Mor Constitutive Activitymentioning

confidence: 99%

Sustained Suppression of Hyperalgesia during Latent Sensitization by μ-, δ-, and κ-opioid receptors and α_2AAdrenergic Receptors: Role of Constitutive Activity

Walwyn¹,

et al. 2016

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Many chronic pain disorders alternate between bouts of pain and periods of remission. The latent sensitization model reproduces this in rodents by showing that the apparent recovery ("remission") from inflammatory or neuropathic pain can be reversed by opioid antagonists. Therefore, this remission represents an opioid receptor-mediated suppression of a sustained hyperalgesic state. To identify the receptors involved, we induced latent sensitization in mice and rats by injecting complete Freund's adjuvant (CFA) in the hindpaw. In WT mice, responses to mechanical stimulation returned to baseline 3 weeks after CFA. In -opioid receptor (MOR) knock-out (KO) mice, responses did not return to baseline but partially recovered from peak hyperalgesia. Antagonists of ␣ 2A -adrenergic and ␦-opioid receptors reinstated hyperalgesia in WT mice and abolished the partial recovery from hyperalgesia in MOR KO mice. In rats, antagonists of ␣ 2A adrenergic and -, ␦-, and -opioid receptors reinstated hyperalgesia during remission from CFA-induced hyperalgesia. Therefore, these four receptors suppress hyperalgesia in latent sensitization. We further demonstrated that suppression of hyperalgesia by MORs was due to their constitutive activity because of the following: (1) CFA-induced hyperalgesia was reinstated by the MOR inverse agonist naltrexone (NTX), but not by its neutral antagonist 6␤-naltrexol; (2) pro-enkephalin, pro-opiomelanocortin, and pro-dynorphin KO mice showed recovery from hyperalgesia and reinstatement by NTX; (3) there was no MOR internalization during remission; (4) MORs immunoprecipitated from the spinal cord during remission had increased Ser 375 phosphorylation; and (5) electrophysiology recordings from dorsal root ganglion neurons collected during remission showed constitutive MOR inhibition of calcium channels.

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Ligands Raise the Constraint That Limits Constitutive Activation in G Protein-coupled Opioid Receptors

Cited by 20 publications

References 34 publications

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Molecular Pharmacology ofδ-Opioid Receptors

Sustained Suppression of Hyperalgesia during Latent Sensitization by μ-, δ-, and κ-opioid receptors and α_2AAdrenergic Receptors: Role of Constitutive Activity

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Ligands Raise the Constraint That Limits Constitutive Activation in G Protein-coupled Opioid Receptors

Cited by 20 publications

References 34 publications

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Molecular Pharmacology ofδ-Opioid Receptors

Sustained Suppression of Hyperalgesia during Latent Sensitization by μ-, δ-, and κ-opioid receptors and α2AAdrenergic Receptors: Role of Constitutive Activity

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Product

Resources

About

Sustained Suppression of Hyperalgesia during Latent Sensitization by μ-, δ-, and κ-opioid receptors and α_2AAdrenergic Receptors: Role of Constitutive Activity