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Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists
Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid(...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi Publishing Corporation
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857906/ https://www.ncbi.nlm.nih.gov/pubmed/24350273 http://dx.doi.org/10.1155/2013/501086 |
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author | Murányi, Marianna Cinar, Resat Kékesi, Orsolya Birkás, Erika Fábián, Gabriella Bozó, Beáta Zentai, András Tóth, Géza Kicsi, Emese Gabriella Mácsai, Mónika Dochnal, Roberta Szabó, Gyula Szücs, Mária |
author_facet | Murányi, Marianna Cinar, Resat Kékesi, Orsolya Birkás, Erika Fábián, Gabriella Bozó, Beáta Zentai, András Tóth, Géza Kicsi, Emese Gabriella Mácsai, Mónika Dochnal, Roberta Szabó, Gyula Szücs, Mária |
author_sort | Murányi, Marianna |
collection | PubMed |
description | Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid(2)-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min after intracerebroventricular (icv) administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the “so-called biased agonism” or “functional selectivity”. |
format | Online Article Text |
id | pubmed-3857906 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-38579062013-12-17 Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists Murányi, Marianna Cinar, Resat Kékesi, Orsolya Birkás, Erika Fábián, Gabriella Bozó, Beáta Zentai, András Tóth, Géza Kicsi, Emese Gabriella Mácsai, Mónika Dochnal, Roberta Szabó, Gyula Szücs, Mária Biomed Res Int Research Article Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid(2)-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min after intracerebroventricular (icv) administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the “so-called biased agonism” or “functional selectivity”. Hindawi Publishing Corporation 2013 2013-11-24 /pmc/articles/PMC3857906/ /pubmed/24350273 http://dx.doi.org/10.1155/2013/501086 Text en Copyright © 2013 Marianna Murányi et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Murányi, Marianna Cinar, Resat Kékesi, Orsolya Birkás, Erika Fábián, Gabriella Bozó, Beáta Zentai, András Tóth, Géza Kicsi, Emese Gabriella Mácsai, Mónika Dochnal, Roberta Szabó, Gyula Szücs, Mária Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists |
title | Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists |
title_full | Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists |
title_fullStr | Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists |
title_full_unstemmed | Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists |
title_short | Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists |
title_sort | ligand-specific regulation of the endogenous mu-opioid receptor by chronic treatment with mu-opioid peptide agonists |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857906/ https://www.ncbi.nlm.nih.gov/pubmed/24350273 http://dx.doi.org/10.1155/2013/501086 |
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