{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:58:41Z","timestamp":1789171121149,"version":"build-2803163510"},"reference-count":57,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T00:00:00Z","timestamp":1636675200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministerio Ciencia Investigacion y Universidades Spain","award":["RT 2018-093677-B-100"],"award-info":[{"award-number":["RT 2018-093677-B-100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Nerve injury produces neuropathic pain through the binding of \u03b12\u03b41 proteins to glutamate N-methyl-D-aspartate receptors (NMDARs). Notably, mice with a targeted deletion of the sigma 1 receptor (\u03c31R) gene do not develop neuropathy, whereas mice lacking the histidine triad nucleotide-binding protein 1 (Hint1) gene exhibit exacerbated allodynia. \u03c31R antagonists more effectively diminish neuropathic pain of spinal origin when administered by intracerebroventricular injection than systemically. Thus, in mice subjected to unilateral sciatic nerve chronic constriction injury (CCI), we studied the participation of \u03c31Rs and HINT1 proteins in the formation of \u03b12\u03b41-NMDAR complexes within the supraspinal periaqueductal gray (PAG). We found that \u03b41 peptides required \u03c31Rs in order to interact with the NMDAR NR1 variant that contains the cytosolic C1 segment. \u03c31R antagonists or low calcium levels provoke the dissociation of \u03c31R-NR1 C1 dimers, while they barely affect the integrity of \u03b41-\u03c31R-NR1 C1 trimers. However, HINT1 does remove \u03b41 peptides from the trimer, thereby facilitating the subsequent dissociation of \u03c31Rs from NMDARs. In \u03c31R\u2212\/\u2212 mice, CCI does not promote the formation of NMDAR-\u03b12\u03b41 complexes and allodynia does not develop. The levels of \u03b12\u03b41-\u03c31R-NMDAR complexes increase in HINT1\u2212\/\u2212 mice and after inducing CCI, degradation of \u03b12\u03b41 proteins is observed. Notably, \u03c31R antagonists but not gabapentinoids alleviate neuropathic pain in these mice. During severe neuropathy, the metabolism of \u03b12\u03b41 proteins may account for the failure of many patients to respond to gabapentinoids. Therefore, \u03c31Rs promote and HINT1 proteins hinder the formation \u03b12\u03b41-NMDAR complexes in the PAG, and hence, the appearance of mechanical allodynia depends on the interplay between these proteins.<\/jats:p>","DOI":"10.3390\/biom11111681","type":"journal-article","created":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T08:10:22Z","timestamp":1636704622000},"page":"1681","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The \u03c31 Receptor and the HINT1 Protein Control \u03b12\u03b41 Binding to Glutamate NMDA Receptors: Implications in Neuropathic Pain"],"prefix":"10.3390","volume":"11","author":[{"given":"Mar\u00eda","family":"Rodr\u00edguez-Mu\u00f1oz","sequence":"first","affiliation":[{"name":"Neuropharmacology, Department of Translational Neuroscience, Cajal Institute, CSIC, 28002 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0671-1156","authenticated-orcid":false,"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":"Yara","family":"Onetti","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0053-258X","authenticated-orcid":false,"given":"Javier","family":"Garz\u00f3n-Ni\u00f1o","sequence":"additional","affiliation":[{"name":"Instituto Cajal, Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Doctor Arce 37, 28002 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17002","DOI":"10.1038\/nrdp.2017.2","article-title":"Neuropathic pain","volume":"3","author":"Colloca","year":"2017","journal-title":"Nat. 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