{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:13:38Z","timestamp":1791220418366,"version":"4.1.0"},"reference-count":35,"publisher":"National Academy of Sciences","issue":"14","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2003,7,8]]},"abstract":"<jats:p>\n                    Sialorphin is an exocrine and endocrine signaling mediator, which has been\n identified by a genomic approach. It is synthesized predominantly in the\n submandibular gland and prostate of adult rats in response to androgen\n steroids and is released locally and systemically in response to stress. We\n now demonstrate that the cell surface molecule to which sialorphin binds\n                    <jats:italic>in vivo<\/jats:italic>\n                    in the rat kidney is the membrane-anchored neutral\n endopeptidase (neprilysin; NEP, EC 3.4.24.11). NEP plays an important role in\n nervous and peripheral tissues, as it turns off several peptide-signaling\n events at the cell surface. We show that sialorphin prevents spinal and renal\n NEP from breaking down its two physiologically relevant substrates, substance\n P and Met-enkephalin\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Sialorphin inhibited the breakdown of\n substance P with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 0.4\u20131 \u03bcM and behaved as a\n competitive inhibitor.\n                    <jats:italic>In vivo<\/jats:italic>\n                    , i.v. sialorphin elicited potent\n antinociceptive responses in two behavioral rat models of injury-induced acute\n and tonic pain, the pin-pain test and formalin test. The analgesia induced by\n 100\u2013200 \u03bcg\/kg doses of sialorphin required the activation of \u03bc-\n and \u03b4-opioid receptors, consistent with the involvement of endogenous\n opioid receptors in enkephalinergic transmission. We conclude that sialorphin\n protects endogenous enkephalins released after nociceptive stimuli by\n inhibiting NEP\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Sialorphin is a natural systemically active\n regulator of NEP activity. Furthermore, our study provides evidence that it is\n a physiological modulator of pain perception after injury and might be the\n progenitor of a new class of therapeutic molecules.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1431850100","type":"journal-article","created":{"date-parts":[[2003,7,8]],"date-time":"2003-07-08T15:18:15Z","timestamp":1057677495000},"page":"8549-8554","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":85,"title":["Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity"],"prefix":"10.1073","volume":"100","author":[{"given":"Catherine","family":"Rougeot","sequence":"first","affiliation":[{"name":"Unit\u00e9 de G\u00e9n\u00e9tique et\r Biochimie du D\u00e9veloppement and\r Unit\u00e9 de Biologie des Interactions\r H\u00f4te-Parasite, Centre National de la Recherche Scientifique,\r Unit\u00e9 de Recherche Associ\u00e9e 1960, Institut Pasteur, 25 Rue du\r Docteur Roux 75724, Paris Cedex 15, France;\r Ethologie Appliqu\u00e9e, 13 Rue du Bois de\r la Champelle, F-54500 Vandoeuvre-l\u00e8s-Nancy, France;\r D\u00e9partement d'Ing\u00e9nierie et\r d'Etudes des Prot\u00e9ines, Commissariat \u00e0 l'Energie\r Atomique\/Saclay, B\u00e2t 152, 91191 Gif\/Yvette, France; and\r Laboratoire de..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micha\u00ebl","family":"Messaoudi","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de G\u00e9n\u00e9tique et\r Biochimie du D\u00e9veloppement and\r Unit\u00e9 de Biologie des Interactions\r H\u00f4te-Parasite, Centre National de la Recherche Scientifique,\r Unit\u00e9 de Recherche Associ\u00e9e 1960, Institut Pasteur, 25 Rue du\r Docteur Roux 75724, Paris Cedex 15, France;\r Ethologie Appliqu\u00e9e, 13 Rue du Bois de\r la Champelle, F-54500 Vandoeuvre-l\u00e8s-Nancy, France;\r D\u00e9partement d'Ing\u00e9nierie et\r d'Etudes des Prot\u00e9ines, Commissariat \u00e0 l'Energie\r Atomique\/Saclay, B\u00e2t 152, 91191 Gif\/Yvette, France; and\r Laboratoire de..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Hermitte","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de G\u00e9n\u00e9tique et\r Biochimie du D\u00e9veloppement and\r Unit\u00e9 de Biologie des Interactions\r H\u00f4te-Parasite, Centre National de la Recherche Scientifique,\r Unit\u00e9 de Recherche Associ\u00e9e 1960, Institut Pasteur, 25 Rue du\r Docteur Roux 75724, Paris Cedex 15, France;\r Ethologie Appliqu\u00e9e, 13 Rue du Bois de\r la Champelle, F-54500 Vandoeuvre-l\u00e8s-Nancy, France;\r D\u00e9partement d'Ing\u00e9nierie et\r d'Etudes des Prot\u00e9ines, Commissariat \u00e0 l'Energie\r Atomique\/Saclay, B\u00e2t 152, 91191 Gif\/Yvette, France; and\r Laboratoire de..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Ga\u00eblle","family":"Rigault","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de G\u00e9n\u00e9tique et\r Biochimie du D\u00e9veloppement and\r Unit\u00e9 de Biologie des Interactions\r H\u00f4te-Parasite, Centre National de la Recherche Scientifique,\r Unit\u00e9 de Recherche Associ\u00e9e 1960, Institut Pasteur, 25 Rue du\r Docteur Roux 75724, Paris Cedex 15, France;\r Ethologie Appliqu\u00e9e, 13 Rue du Bois de\r la Champelle, F-54500 Vandoeuvre-l\u00e8s-Nancy, France;\r D\u00e9partement d'Ing\u00e9nierie et\r d'Etudes des Prot\u00e9ines, Commissariat \u00e0 l'Energie\r Atomique\/Saclay, B\u00e2t 152, 91191 Gif\/Yvette, France; and\r Laboratoire de..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Blisnick","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de G\u00e9n\u00e9tique et\r Biochimie du D\u00e9veloppement and\r Unit\u00e9 de Biologie des Interactions\r H\u00f4te-Parasite, Centre National de la Recherche Scientifique,\r Unit\u00e9 de Recherche Associ\u00e9e 1960, Institut Pasteur, 25 Rue du\r Docteur Roux 75724, Paris Cedex 15, France;\r Ethologie Appliqu\u00e9e, 13 Rue du Bois de\r la Champelle, F-54500 Vandoeuvre-l\u00e8s-Nancy, France;\r D\u00e9partement d'Ing\u00e9nierie et\r d'Etudes des Prot\u00e9ines, Commissariat \u00e0 l'Energie\r Atomique\/Saclay, B\u00e2t 152, 91191 Gif\/Yvette, France; and\r Laboratoire de..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Dugave","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de G\u00e9n\u00e9tique et\r Biochimie du D\u00e9veloppement and\r Unit\u00e9 de Biologie des Interactions\r H\u00f4te-Parasite, Centre National de la Recherche Scientifique,\r Unit\u00e9 de Recherche Associ\u00e9e 1960, Institut Pasteur, 25 Rue du\r Docteur Roux 75724, Paris Cedex 15, France;\r Ethologie Appliqu\u00e9e, 13 Rue du Bois de\r la Champelle, F-54500 Vandoeuvre-l\u00e8s-Nancy, France;\r D\u00e9partement d'Ing\u00e9nierie et\r d'Etudes des Prot\u00e9ines, Commissariat \u00e0 l'Energie\r Atomique\/Saclay, B\u00e2t 152, 91191 Gif\/Yvette, France; and\r Laboratoire de..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Desor","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de G\u00e9n\u00e9tique et\r Biochimie du D\u00e9veloppement and\r Unit\u00e9 de Biologie des Interactions\r H\u00f4te-Parasite, Centre National de la Recherche Scientifique,\r Unit\u00e9 de Recherche Associ\u00e9e 1960, Institut Pasteur, 25 Rue du\r Docteur Roux 75724, Paris Cedex 15, France;\r Ethologie Appliqu\u00e9e, 13 Rue du Bois de\r la Champelle, F-54500 Vandoeuvre-l\u00e8s-Nancy, France;\r D\u00e9partement d'Ing\u00e9nierie et\r d'Etudes des Prot\u00e9ines, Commissariat \u00e0 l'Energie\r Atomique\/Saclay, B\u00e2t 152, 91191 Gif\/Yvette, France; 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