Modulation of NMDA receptor activity by CR4056, an imidazoline-2 receptor ligand with analgesic properties

CR4056 is an imidazoline-2 receptor ligand having potent analgesic activity and synergistic effect with opioids. Very recently it has been found that CR4056 can revert the cognitive impairment in animal models of Alzheimer's disease (AD). Since several lines of evidence highlight the importance...

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Main Authors: Giulia Puja, Gabriele Losi, Lucio Rovati, Marco Lanza, Gianfranco Caselli, Rita Bardoni
Format: Article
Language:English
Published: Frontiers Media S.A. 2022-09-01
Series:Frontiers in Pain Research
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fpain.2022.1003068/full
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author Giulia Puja
Gabriele Losi
Lucio Rovati
Marco Lanza
Gianfranco Caselli
Rita Bardoni
author_facet Giulia Puja
Gabriele Losi
Lucio Rovati
Marco Lanza
Gianfranco Caselli
Rita Bardoni
author_sort Giulia Puja
collection DOAJ
description CR4056 is an imidazoline-2 receptor ligand having potent analgesic activity and synergistic effect with opioids. Very recently it has been found that CR4056 can revert the cognitive impairment in animal models of Alzheimer's disease (AD). Since several lines of evidence highlight the importance of NMDAR modulators in nociceptive signaling and in AD progression, we considered as important to investigate the effects of CR4056 on NMDAR activity. In primary culture of cortical neurons, application of NMDA and glycine elicits a current that is decreased in a dose-dependent fashion by CR4056 (IC50 5.3 ± 0.1 µM). CR4056 antagonism is reversible, not competitive and voltage-independent and it is not blocked by pertussis toxin. CR4056 interacts with the co-agonist glycine site in a competitive way, indeed high glycine concentrations diminish its effect. Fibroblasts expressing different recombinant NMDA receptors are differently modulated by CR4056: the potency and the efficacy of the compound are higher in GluN1- GluN2B than in GluN1-GluN2A containing receptors. In lamina II neurons of spinal cord slices, single stimulation of afferent fibers evokes an NMDA-mediated current that is inhibited by 10 µM CR4056. Repetitive stimulation of the dorsal root at high frequency and high intensity produces a firing activity that is significatively depressed by CR4056. Taken together, our results broad the understanding of the molecular mechanisms of CR4056 analgesic activity, involving the modulation of NMDAR activity. Therefore, we propose that the analgesic action of CR4056 and the neuroprotective effects in AD models may be mediated also by NMDAR inhibition.
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spelling doaj.art-85aed6d993bf4ec38c2872100671727b2022-12-22T02:36:40ZengFrontiers Media S.A.Frontiers in Pain Research2673-561X2022-09-01310.3389/fpain.2022.10030681003068Modulation of NMDA receptor activity by CR4056, an imidazoline-2 receptor ligand with analgesic propertiesGiulia Puja0Gabriele Losi1Lucio Rovati2Marco Lanza3Gianfranco Caselli4Rita Bardoni5Department of Life Sciences, University of Modena and Reggio Emilia, Modena, ItalyDepartment of Physics, Institute of Nanoscience -CNR (CNR-NANO S3), Modena, ItalyRottapharm Biotech, Monza, ItalyRottapharm Biotech, Monza, ItalyRottapharm Biotech, Monza, ItalyDepartment of Biomedical, Metabolic and Neural Sciences,University of Modena and Reggio Emilia, Modena, ItalyCR4056 is an imidazoline-2 receptor ligand having potent analgesic activity and synergistic effect with opioids. Very recently it has been found that CR4056 can revert the cognitive impairment in animal models of Alzheimer's disease (AD). Since several lines of evidence highlight the importance of NMDAR modulators in nociceptive signaling and in AD progression, we considered as important to investigate the effects of CR4056 on NMDAR activity. In primary culture of cortical neurons, application of NMDA and glycine elicits a current that is decreased in a dose-dependent fashion by CR4056 (IC50 5.3 ± 0.1 µM). CR4056 antagonism is reversible, not competitive and voltage-independent and it is not blocked by pertussis toxin. CR4056 interacts with the co-agonist glycine site in a competitive way, indeed high glycine concentrations diminish its effect. Fibroblasts expressing different recombinant NMDA receptors are differently modulated by CR4056: the potency and the efficacy of the compound are higher in GluN1- GluN2B than in GluN1-GluN2A containing receptors. In lamina II neurons of spinal cord slices, single stimulation of afferent fibers evokes an NMDA-mediated current that is inhibited by 10 µM CR4056. Repetitive stimulation of the dorsal root at high frequency and high intensity produces a firing activity that is significatively depressed by CR4056. Taken together, our results broad the understanding of the molecular mechanisms of CR4056 analgesic activity, involving the modulation of NMDAR activity. Therefore, we propose that the analgesic action of CR4056 and the neuroprotective effects in AD models may be mediated also by NMDAR inhibition.https://www.frontiersin.org/articles/10.3389/fpain.2022.1003068/fullNMDA receptorpainelectrophysiologyneuronal culturesspinal cordimidazoline-2 receptor ligands
spellingShingle Giulia Puja
Gabriele Losi
Lucio Rovati
Marco Lanza
Gianfranco Caselli
Rita Bardoni
Modulation of NMDA receptor activity by CR4056, an imidazoline-2 receptor ligand with analgesic properties
Frontiers in Pain Research
NMDA receptor
pain
electrophysiology
neuronal cultures
spinal cord
imidazoline-2 receptor ligands
title Modulation of NMDA receptor activity by CR4056, an imidazoline-2 receptor ligand with analgesic properties
title_full Modulation of NMDA receptor activity by CR4056, an imidazoline-2 receptor ligand with analgesic properties
title_fullStr Modulation of NMDA receptor activity by CR4056, an imidazoline-2 receptor ligand with analgesic properties
title_full_unstemmed Modulation of NMDA receptor activity by CR4056, an imidazoline-2 receptor ligand with analgesic properties
title_short Modulation of NMDA receptor activity by CR4056, an imidazoline-2 receptor ligand with analgesic properties
title_sort modulation of nmda receptor activity by cr4056 an imidazoline 2 receptor ligand with analgesic properties
topic NMDA receptor
pain
electrophysiology
neuronal cultures
spinal cord
imidazoline-2 receptor ligands
url https://www.frontiersin.org/articles/10.3389/fpain.2022.1003068/full
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