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Disruption of 5-HT(2A) Receptor-PDZ Protein Interactions Alleviates Mechanical Hypersensitivity in Carrageenan-Induced Inflammation in Rats

Despite common pathophysiological mechanisms, inflammatory and neuropathic pain do not respond equally to the analgesic effect of antidepressants, except for selective serotonin reuptake inhibitors (SSRIs), which show a limited efficacy in both conditions. We previously demonstrated that an interfer...

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Autores principales: Wattiez, Anne-Sophie, Pichon, Xavier, Dupuis, Amandine, Hernández, Alejandro, Privat, Anne-Marie, Aissouni, Youssef, Chalus, Maryse, Pelissier, Teresa, Eschalier, Alain, Marin, Philippe, Courteix, Christine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776748/
https://www.ncbi.nlm.nih.gov/pubmed/24058620
http://dx.doi.org/10.1371/journal.pone.0074661
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author Wattiez, Anne-Sophie
Pichon, Xavier
Dupuis, Amandine
Hernández, Alejandro
Privat, Anne-Marie
Aissouni, Youssef
Chalus, Maryse
Pelissier, Teresa
Eschalier, Alain
Marin, Philippe
Courteix, Christine
author_facet Wattiez, Anne-Sophie
Pichon, Xavier
Dupuis, Amandine
Hernández, Alejandro
Privat, Anne-Marie
Aissouni, Youssef
Chalus, Maryse
Pelissier, Teresa
Eschalier, Alain
Marin, Philippe
Courteix, Christine
author_sort Wattiez, Anne-Sophie
collection PubMed
description Despite common pathophysiological mechanisms, inflammatory and neuropathic pain do not respond equally to the analgesic effect of antidepressants, except for selective serotonin reuptake inhibitors (SSRIs), which show a limited efficacy in both conditions. We previously demonstrated that an interfering peptide (TAT-2ASCV) disrupting the interaction between 5-HT(2A) receptors and its associated PDZ proteins (e.g. PSD-95) reveals a 5-HT(2A) receptor-mediated anti-hyperalgesic effect and enhances the efficacy of fluoxetine (a SSRI) in diabetic neuropathic pain conditions in rats. Here, we have examined whether the same strategy would be useful to treat inflammatory pain. Sub-chronic inflammatory pain was induced by injecting λ-carrageenan (100 µl, 2%) into the left hind paw of the rat. Mechanical hyperalgesia was assessed after acute treatment with TAT-2ASCV or/and fluoxetine (SSRI) 2.5 h after λ-carrageenan injection. Possible changes in the level of 5-HT(2A) receptors and its associated PDZ protein PSD-95 upon inflammation induction were quantified by Western blotting in dorsal horn spinal cord. Administration of TAT-2ASCV peptide (100 ng/rat, intrathecally) but not fluoxetine (10 mg/kg, intraperitoneally) relieves mechanical hyperalgesia (paw pressure test) in inflamed rats. This anti-hyperalgesic effect involves spinal 5-HT(2A) receptors and GABAergic interneurons as it is abolished by a 5-HT(2A) antagonist (M100907, 150 ng/rat, intrathecally) and a GABA(A) antagonist, (bicuculline, 3 µg/rat, intrathecally). We also found a decreased expression of 5-HT(2A) receptors in the dorsal spinal cord of inflamed animals which could not be rescued by TAT-2ASCV injection, while the amount of PSD-95 was not affected by inflammatory pain. Finally, the coadministration of fluoxetine does not further enhance the anti-hyperalgesic effect of TAT-2ASCV peptide. This study reveals a role of the interactions between 5-HT(2A) receptors and PDZ proteins in the pathophysiological pathways of inflammatory pain and opens new perspectives in its control thanks to molecules disrupting 5-HT(2A) receptor/PDZ protein interactions.
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spelling pubmed-37767482013-09-20 Disruption of 5-HT(2A) Receptor-PDZ Protein Interactions Alleviates Mechanical Hypersensitivity in Carrageenan-Induced Inflammation in Rats Wattiez, Anne-Sophie Pichon, Xavier Dupuis, Amandine Hernández, Alejandro Privat, Anne-Marie Aissouni, Youssef Chalus, Maryse Pelissier, Teresa Eschalier, Alain Marin, Philippe Courteix, Christine PLoS One Research Article Despite common pathophysiological mechanisms, inflammatory and neuropathic pain do not respond equally to the analgesic effect of antidepressants, except for selective serotonin reuptake inhibitors (SSRIs), which show a limited efficacy in both conditions. We previously demonstrated that an interfering peptide (TAT-2ASCV) disrupting the interaction between 5-HT(2A) receptors and its associated PDZ proteins (e.g. PSD-95) reveals a 5-HT(2A) receptor-mediated anti-hyperalgesic effect and enhances the efficacy of fluoxetine (a SSRI) in diabetic neuropathic pain conditions in rats. Here, we have examined whether the same strategy would be useful to treat inflammatory pain. Sub-chronic inflammatory pain was induced by injecting λ-carrageenan (100 µl, 2%) into the left hind paw of the rat. Mechanical hyperalgesia was assessed after acute treatment with TAT-2ASCV or/and fluoxetine (SSRI) 2.5 h after λ-carrageenan injection. Possible changes in the level of 5-HT(2A) receptors and its associated PDZ protein PSD-95 upon inflammation induction were quantified by Western blotting in dorsal horn spinal cord. Administration of TAT-2ASCV peptide (100 ng/rat, intrathecally) but not fluoxetine (10 mg/kg, intraperitoneally) relieves mechanical hyperalgesia (paw pressure test) in inflamed rats. This anti-hyperalgesic effect involves spinal 5-HT(2A) receptors and GABAergic interneurons as it is abolished by a 5-HT(2A) antagonist (M100907, 150 ng/rat, intrathecally) and a GABA(A) antagonist, (bicuculline, 3 µg/rat, intrathecally). We also found a decreased expression of 5-HT(2A) receptors in the dorsal spinal cord of inflamed animals which could not be rescued by TAT-2ASCV injection, while the amount of PSD-95 was not affected by inflammatory pain. Finally, the coadministration of fluoxetine does not further enhance the anti-hyperalgesic effect of TAT-2ASCV peptide. This study reveals a role of the interactions between 5-HT(2A) receptors and PDZ proteins in the pathophysiological pathways of inflammatory pain and opens new perspectives in its control thanks to molecules disrupting 5-HT(2A) receptor/PDZ protein interactions. Public Library of Science 2013-09-18 /pmc/articles/PMC3776748/ /pubmed/24058620 http://dx.doi.org/10.1371/journal.pone.0074661 Text en © 2013 Wattiez et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wattiez, Anne-Sophie
Pichon, Xavier
Dupuis, Amandine
Hernández, Alejandro
Privat, Anne-Marie
Aissouni, Youssef
Chalus, Maryse
Pelissier, Teresa
Eschalier, Alain
Marin, Philippe
Courteix, Christine
Disruption of 5-HT(2A) Receptor-PDZ Protein Interactions Alleviates Mechanical Hypersensitivity in Carrageenan-Induced Inflammation in Rats
title Disruption of 5-HT(2A) Receptor-PDZ Protein Interactions Alleviates Mechanical Hypersensitivity in Carrageenan-Induced Inflammation in Rats
title_full Disruption of 5-HT(2A) Receptor-PDZ Protein Interactions Alleviates Mechanical Hypersensitivity in Carrageenan-Induced Inflammation in Rats
title_fullStr Disruption of 5-HT(2A) Receptor-PDZ Protein Interactions Alleviates Mechanical Hypersensitivity in Carrageenan-Induced Inflammation in Rats
title_full_unstemmed Disruption of 5-HT(2A) Receptor-PDZ Protein Interactions Alleviates Mechanical Hypersensitivity in Carrageenan-Induced Inflammation in Rats
title_short Disruption of 5-HT(2A) Receptor-PDZ Protein Interactions Alleviates Mechanical Hypersensitivity in Carrageenan-Induced Inflammation in Rats
title_sort disruption of 5-ht(2a) receptor-pdz protein interactions alleviates mechanical hypersensitivity in carrageenan-induced inflammation in rats
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776748/
https://www.ncbi.nlm.nih.gov/pubmed/24058620
http://dx.doi.org/10.1371/journal.pone.0074661
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