{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T02:35:15Z","timestamp":1781404515831,"version":"3.54.1"},"reference-count":92,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T00:00:00Z","timestamp":1672272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministerio de Ciencia e Innovaci\u00f3n Plan Nacional I+D+i","award":["RT 2018-093677-B-100"],"award-info":[{"award-number":["RT 2018-093677-B-100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The opioid peptide \u03b2-endorphin coexists in the pituitary and brain in its \u03b1N-acetylated form, which does not bind to opioid receptors. We now report that these neuropeptides exhibited opposite effects in in vivo paradigms, in which ligands of the sigma type 1 receptor (\u03c31R) displayed positive effects. Thus, \u03b1N-acetyl \u03b2-Endorphin reduced vascular infarct caused by permanent unilateral middle cerebral artery occlusion and diminished the incidence of N-methyl-D-aspartate acid-promoted convulsive syndrome and mechanical allodynia caused by unilateral chronic constriction of the sciatic nerve. Moreover, \u03b1N-acetyl \u03b2-Endorphin reduced the analgesia of morphine, \u03b2-Endorphin and clonidine but enhanced that of DAMGO. All these effects were counteracted by \u03b2-Endorphin and absent in \u03c31R\u2212\/\u2212 mice. We observed that \u03c31Rs negatively regulate mu-opioid receptor (MOR)-mediated morphine analgesia by binding and sequestering G proteins. In this scenario, \u03b2-Endorphin promoted the exchange of \u03c32Rs by G proteins at \u03c31R oligomers and increased the regulation of G proteins by MORs. The opposite was observed for the \u03b1N-acetyl derivative, as \u03c31R oligomerization decreased and \u03c32R binding was favored, which displaced G proteins; thus, MOR-regulated transduction was reduced. Our findings suggest that the pharmacological \u03b2-Endorphin-specific epsilon receptor is a \u03c31R-regulated MOR and that \u03b2-Endorphin and \u03b1N-acetyl \u03b2-Endorphin are endogenous ligands of \u03c31R.<\/jats:p>","DOI":"10.3390\/ijms24010582","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T03:26:11Z","timestamp":1672370771000},"page":"582","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["\u03b1N-Acetyl \u03b2-Endorphin Is an Endogenous Ligand of \u03c31Rs That Regulates Mu-Opioid Receptor Signaling by Exchanging G Proteins for \u03c32Rs in \u03c31R Oligomers"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0053-258X","authenticated-orcid":false,"given":"Javier","family":"Garz\u00f3n-Ni\u00f1o","sequence":"first","affiliation":[{"name":"Neuropharmacology, Department of Translational Neuroscience, Cajal Institute, CSIC, 28002 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsa","family":"Cort\u00e9s-Montero","sequence":"additional","affiliation":[{"name":"Neuropharmacology, Department of Translational Neuroscience, Cajal Institute, CSIC, 28002 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Rodr\u00edguez-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Neuropharmacology, Department of Translational Neuroscience, Cajal Institute, CSIC, 28002 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7211-4504","authenticated-orcid":false,"given":"Pilar","family":"S\u00e1nchez-Bl\u00e1zquez","sequence":"additional","affiliation":[{"name":"Neuropharmacology, Department of Translational Neuroscience, Cajal Institute, CSIC, 28002 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1073\/pnas.73.4.1145","article-title":"Isolation and structure of an untriakontapeptide with opiate activity from camel pituitary glands","volume":"73","author":"Li","year":"1976","journal-title":"Proc. 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