{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T01:30:48Z","timestamp":1777944648848,"version":"3.51.4"},"reference-count":54,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2016,1,1]],"date-time":"2016-01-01T00:00:00Z","timestamp":1451606400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Mol Pain"],"published-print":{"date-parts":[[2016,1,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Opioids are the gold standard for the treatment of acute pain despite serious side effects in the central and enteric nervous system. \u00b5-opioid receptors (MOPs) are expressed and functional at the terminals of sensory axons, when activated by exogenous or endogenous ligands. However, the presence and function of MOP along nociceptive axons remains controversial particularly in na\u00efve animals. Here, we characterized axonal MOPs by immunofluorescence, ultrastructural, and functional analyses. Furthermore, we evaluated hypertonic saline as a possible enhancer of opioid receptor function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Comparative immunolabeling showed that, among several tested antibodies, which all provided specific MOP detection in the rat central nervous system (CNS), only one monoclonal MOP-antibody yielded specificity and reproducibility for MOP detection in the rat peripheral nervous system including the sciatic nerve. Double immunolabeling documented that MOP immunoreactivity was confined to calcitonin gene-related peptide (CGRP) positive fibers and fiber bundles. Almost identical labeling and double labeling patterns were found using mcherry-immunolabeling on sciatic nerves of mice producing a MOP-mcherry fusion protein (MOP-mcherry knock-in mice). Preembedding immunogold electron microscopy on MOP-mcherry knock-in sciatic nerves indicated presence of MOP in cytoplasm and at membranes of unmyelinated axons. Application of [D-Ala\n                      <jats:sup>2<\/jats:sup>\n                      , N-MePhe\n                      <jats:sup>4<\/jats:sup>\n                      , Gly-ol]-enkephalin (DAMGO) or fentanyl dose-dependently inhibited depolarization-induced CGRP release from rat sciatic nerve axons ex vivo, which was blocked by naloxone. When the lipophilic opioid fentanyl was applied perisciatically in na\u00efve Wistar rats, mechanical nociceptive thresholds increased. Subthreshold doses of fentanyl or the hydrophilic opioid DAMGO were only effective if injected together with hypertonic saline. In\u00a0vitro, using \u03b2-arrestin-2\/MOP double-transfected human embryonic kidney cells, DAMGO as well as fentanyl lead to a recruitment of \u03b2-arrestin-2 to the membrane followed by a \u03b2-arrestin-2 reappearance in the cytosol and MOP internalization. Pretreatment with hypertonic saline prevented MOP internalization.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>MOPs are present and functional in the axonal membrane from na\u00efve animals. Hypertonic saline acutely decreases ligand-induced internalization of MOP and thereby might improve MOP function. Further studies should explore potential clinical applications of opioids together with enhancers for regional analgesia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/1744806916628734","type":"journal-article","created":{"date-parts":[[2016,3,1]],"date-time":"2016-03-01T23:23:56Z","timestamp":1456874636000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":26,"title":["Functional and structural characterization of axonal opioid receptors as targets for analgesia"],"prefix":"10.1177","volume":"12","author":[{"given":"Egle M","family":"Mambretti","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, University Hospital of Wuerzburg, Germany"},{"name":"Institute of Anatomy and Cell Biology, University of Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin","family":"Kistner","sequence":"additional","affiliation":[{"name":"Institute of Physiology and Pathophysiology, University of Erlangen-Nuremberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanie","family":"Mayer","sequence":"additional","affiliation":[{"name":"Institute for Pharmacology and Toxicology & Bio-Imaging Center\/Rudolf-Virchow Center, University of Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominique","family":"Massotte","sequence":"additional","affiliation":[{"name":"Institut des Neurosciences Cellulaires et Int\u00e9gratives, CNRS UPR, Strasbourg Cedex, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigitte L","family":"Kieffer","sequence":"additional","affiliation":[{"name":"Douglas Research Center, Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada"},{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, Universit\u00e9 de Strasbourg, Illkirch, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carsten","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Institute for Pharmacology and Toxicology & Bio-Imaging Center\/Rudolf-Virchow Center, University of Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter W","family":"Reeh","sequence":"additional","affiliation":[{"name":"Institute of Physiology and Pathophysiology, University of Erlangen-Nuremberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Brack","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Hospital of Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esther","family":"Asan","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Cell Biology, University of Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heike 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