{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:03:39Z","timestamp":1791205419973,"version":"4.1.0"},"reference-count":62,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2012,8,24]],"date-time":"2012-08-24T00:00:00Z","timestamp":1345766400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["MA 2437\/2\u20101"],"award-info":[{"award-number":["MA 2437\/2\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["STE 477\/9\u20101"],"award-info":[{"award-number":["STE 477\/9\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:p>\n                    Inflammatory pain can be controlled by endogenous opioid peptides. Here we blocked the degradation of opioids in peripheral injured tissue to locally augment this physiological system. In rats with hindpaw inflammation, inhibitors of aminopeptidase N (APN; bestatin) or neutral endopeptidase (NEP; thiorphan), and a dual inhibitor, NH\n                    <jats:sub>2<\/jats:sub>\n                    \u2010CH\u2010Ph\u2010P(O)(OH)CH\n                    <jats:sub>2<\/jats:sub>\n                    \u2010CH\u2010CH\n                    <jats:sub>2<\/jats:sub>\n                    Ph(p\u2010Ph)\u2010CONH\u2010CH\u2010CH\n                    <jats:sub>3<\/jats:sub>\n                    \u2010COOH (P8B), were applied to injured paws. Combined bestatin (1.25\u20135 mg)\/thiorphan (0.2\u20130.8 mg) or P8B (0.0625\u20131 mg) alone elevated mechanical nociceptive thresholds to 307 and 227% of vehicle\u2010treated controls, respectively. This analgesia was abolished by antibodies to methionine\u2010enkephalin, leucine\u2010enkephalin, and dynorphin A 1\u201317, by peripherally restricted and by selective \u03bc\u2010, \u03b4\u2010, and \u03ba\u2010opioid receptor antagonists. Flow cytometry and photospectrometry revealed expression and metabolic activity of APN and NEP on macrophages, granulocytes, and sciatic nerves from inflamed tissue. Radioimmunoassays showed that inhibition of leukocytic APN and NEP by bestatin (5\u2013500 \u03bcM)\/thiorphan (1\u2013100 \u03bcM) combinations or by P8B (1\u2013100 \u03bcM) prevented the degradation of enkephalins. Blockade of neuronal peptidases by bestatin (0.5\u201310 mM)\/thiorphan (0.1\u20135 mM) or by P8B (0.1\u201310 mM) additionally hindered dynorphin A 1\u201317 catabolism. Thus, leukocytes and peripheral nerves are important sources of APN and NEP in inflamed tissue, and their blockade promotes peripheral opioid analgesia.\u2014Schreiter, A., Gore, C., Labuz, D., Fournie\u2010Zaluski, M.\u2010C., Roques, B. P., Stein, C., Machelska, H. Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    26, 5161\u20135171 (2012).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.12-208678","type":"journal-article","created":{"date-parts":[[2012,8,24]],"date-time":"2012-08-24T22:43:27Z","timestamp":1345848207000},"page":"5161-5171","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue"],"prefix":"10.1096","volume":"26","author":[{"given":"Anja","family":"Schreiter","sequence":"first","affiliation":[{"name":"Klinik f\u00fcr An\u00e4sthesiologie und Operative Intensivmedizin Freie Universit\u00e4t Berlin, Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Campus Benjamin Franklin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Gore","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr An\u00e4sthesiologie und Operative Intensivmedizin Freie Universit\u00e4t Berlin, Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Campus Benjamin Franklin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominika","family":"Labuz","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr An\u00e4sthesiologie und Operative Intensivmedizin Freie Universit\u00e4t Berlin, Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Campus Benjamin Franklin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Claude","family":"Fournie\u2010Zaluski","sequence":"additional","affiliation":[{"name":"Pharmaleads SAS Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard P.","family":"Roques","sequence":"additional","affiliation":[{"name":"Pharmaleads SAS Paris France"},{"name":"Universit\u00e9 Paris Descartes Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Stein","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr An\u00e4sthesiologie und Operative Intensivmedizin Freie Universit\u00e4t Berlin, Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Campus Benjamin Franklin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halina","family":"Machelska","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr An\u00e4sthesiologie und Operative Intensivmedizin Freie Universit\u00e4t Berlin, Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Campus Benjamin Franklin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,8,24]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp0908913"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3491-11.2011"},{"key":"e_1_2_7_4_1","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.c7086","article-title":"Cardiovascular safety of non\u2010steroidal anti\u2010inflammatory drugs: network meta\u2010analysis","volume":"342","author":"Trelle S.","year":"2011","journal-title":"BMJ"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.110.003145"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.15.5935"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119506"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200108000-00036"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5728(03)00213-3"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4349-05.2006"},{"key":"e_1_2_7_11_1","first-page":"1065","article-title":"Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain","volume":"118","author":"Z\u00f6llner C.","year":"2008","journal-title":"J. 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