Modulation of Silent and Constitutively Active Nociceptin/Orphanin FQ Receptors by Potent Receptor Antagonists and Na<sup>+</sup> Ions in Rat Sympathetic Neurons

Mahmoud, Saifeldin; Margas, Wojciech; Trapella, Claudio; Calò, Girolamo; Ruiz‐Velasco, Victor

doi:10.1124/mol.109.062208

Cited by 22 publications

(22 citation statements)

References 37 publications

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“…Specifically, intracerebroventricular (icv) administration of the peptide NOP-R antagonist, UFP-101, enhanced and prolonged, respectively, ACTH and CORT responses to acute restraint (Leggett et al, 2007). This supports the notion that nociceptin signaling exerts a restraining effect on the HPA response to stressors (Koster et al, 1999), although under certain conditions UFP-101 acts as a partial agonist at the NOP-R receptor, potentially mimicking the effects of OFQ/N (Mahmoud et al, 2010). For example, under conditions in which NOP-R was highly expressed and constitutively active, UFP-101 inhibited Ca 2+ currents in cultured, stellate ganglion neurons in a manner similar to that of OFQ/N (Mahmoud et al, 2010).…”

Section: Ofq/n and The Hypothalamic-pituitary-adrenal Axissupporting

confidence: 78%

“…This supports the notion that nociceptin signaling exerts a restraining effect on the HPA response to stressors (Koster et al, 1999), although under certain conditions UFP-101 acts as a partial agonist at the NOP-R receptor, potentially mimicking the effects of OFQ/N (Mahmoud et al, 2010). For example, under conditions in which NOP-R was highly expressed and constitutively active, UFP-101 inhibited Ca 2+ currents in cultured, stellate ganglion neurons in a manner similar to that of OFQ/N (Mahmoud et al, 2010). On the other hand, UFP-101 blocked OFQ/N-mediated Ca 2+ current inhibition in control cells expressing NOP-R at physiological levels (Mahmoud et al, 2010).…”

Section: Ofq/n and The Hypothalamic-pituitary-adrenal Axissupporting

confidence: 78%

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The role of orphanin FQ/nociceptin in neuroplasticity: relationship to stress, anxiety and neuroinflammation

Mallimo

Kusnecov

2013

Front. Cell. Neurosci.

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The neuropeptide, orphanin FQ/nociceptin (OFQ/N or simply, nociceptin), is expressed in both neuronal and non-neuronal tissue, including the immune system. In the brain, OFQ/N has been investigated in relation to stress, anxiety, learning and memory, and addiction. More recently, it has also been found that OFQ/N influences glial cell functions, including oligodendrocytes, astrocytes, and microglial cells. However, this latter research is relatively small, but potentially important, when observations regarding the relationship of OFQ/N to stress and emotional functions is taken into consideration and integrated with the growing evidence for its involvement in cells that mediate inflammatory events. This review will first provide an overview and understanding of how OFQ/N has been implicated in the HPA axis response to stress, followed by an understanding of its influence on natural and learned anxiety-like behavior. What emerges from an examination of the literature is a neuropeptide that appears to counteract anxiogenic influences, but paradoxically, without attenuating HPA axis responses generated in response to stress. Studies utilized both central administration of OFQ/N, which was shown to activate the HPA axis, as well as antagonism of NOP-R, the OFQ/N receptor. In contrast, antagonist or transgenic OFQ/N or NOP-R knockout studies, showed augmentation of HPA axis responses to stress, suggesting that OFQ/N may be needed to control the magnitude of the HPA axis response to stress. Investigations of behavior in standard exploratory tests of anxiogenic behavior (eg., elevated plus maze) or learned fear responses have suggested that OFQ/N is needed to attenuate fear or anxiety-like behavior. However, some discrepant observations, in particular, those that involve appetitive behaviors, suggest a failure of NOP-R deletion to increase anxiety. However, it is also suggested that OFQ/N may operate in an anxiolytic manner when initial anxiogenic triggers (eg., the neuropeptide CRH) are initiated. Finally, the regulatory functions of OFQ/N in relation to emotion-related behaviors may serve to counteract potential neuroinflammatory events in the brain. This appears to be evident within the glial cell environment of the brain, since OFQ/N has been shown to reduce the production of proinflammatory cellular and cytokine events. Given that both OFQ/N and glial cells are activated in response to stress, it is possible that there is a possible convergence of these two systems that has important repercussions for behavior and neuroplasticity.

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Section: Ofq/n and The Hypothalamic-pituitary-adrenal Axissupporting

confidence: 78%

Section: Ofq/n and The Hypothalamic-pituitary-adrenal Axissupporting

confidence: 78%

The role of orphanin FQ/nociceptin in neuroplasticity: relationship to stress, anxiety and neuroinflammation

Mallimo

Kusnecov

2013

Front. Cell. Neurosci.

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“…The DOR was the first of the opioid receptors where a peptide antagonist, [N,N9-diallylTry 1 .Aib 2,3 ,Leu 5 ]enkephalin (ICI174864), was found to decrease signaling even in the absence of agonist (Costa and Herz, 1989). More recently constitutive activity of expressed MOR was demonstrated using b-chlornaltrexamine (b-CNA) in HEK293 cells (Burford, et al, 2000) and b-funaltrexamine (b-FNA) in GH3 cells ) and using G protein modulation of calcium channel currents in neurons overexpressing MOR (Mahmoud et al, 2010), although it should be noted that the level of constitutive activity that has been detected is relatively small even when MOR was overexpressed.…”

Section: Increased Constitutive Activity Of M-opioid Receptorsmentioning

confidence: 99%

Regulation ofµ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance

et al. 2013

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“…Electrophysiological recording of neurons, in which overexpression of the receptor was induced by microinjection of coding cDNA, demonstrated the antagonist C-24 to have inverse agonist activity, indicative of constitutive activation of NOP receptor when overexpressed (Mahmoud et al, 2010). In another study, in which the ability to constitutively activate G-protein-coupled pathways was investigated in a series of NOP receptor point mutations, only the N133W mutant displayed increased ligandindependent signaling (Kam et al, 2002).…”

Section: A Nociceptin Opioid Peptide Receptor Proteinmentioning

confidence: 99%

“…This strongly suggests constitutively active NOP receptors in transfected neurons. In these neurons C-24 not only antagonized the N/OFQ inhibitory effect but also exerted inverse agonism, as measured by the loss of tonic Ca 2+ current inhibition (Mahmoud et al, 2010).…”

Section: S]mentioning

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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Modulation of Silent and Constitutively Active Nociceptin/Orphanin FQ Receptors by Potent Receptor Antagonists and Na⁺ Ions in Rat Sympathetic Neurons

Cited by 22 publications

References 37 publications

The role of orphanin FQ/nociceptin in neuroplasticity: relationship to stress, anxiety and neuroinflammation

The role of orphanin FQ/nociceptin in neuroplasticity: relationship to stress, anxiety and neuroinflammation

Regulation ofµ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance

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

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Modulation of Silent and Constitutively Active Nociceptin/Orphanin FQ Receptors by Potent Receptor Antagonists and Na+ Ions in Rat Sympathetic Neurons

Cited by 22 publications

References 37 publications

The role of orphanin FQ/nociceptin in neuroplasticity: relationship to stress, anxiety and neuroinflammation

The role of orphanin FQ/nociceptin in neuroplasticity: relationship to stress, anxiety and neuroinflammation

Regulation ofµ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance

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

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Modulation of Silent and Constitutively Active Nociceptin/Orphanin FQ Receptors by Potent Receptor Antagonists and Na⁺ Ions in Rat Sympathetic Neurons