{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:25:22Z","timestamp":1791192322530,"version":"4.1.0"},"reference-count":40,"publisher":"National Academy of Sciences","issue":"25","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,6,22]]},"abstract":"<jats:p>\n                    Ligand-directed signaling has been suggested as a basis for the differences in responses evoked by otherwise receptor-selective agonists. The underlying mechanisms are not understood, yet clearer definition of this concept may be helpful in the development of novel, pathway-selective therapeutic agents. We previously showed that \u03ba-opioid receptor activation of JNK by one class of ligand, but not another, caused persistent receptor inactivation. In the current study, we found that the \u03bc-opioid receptor (MOR) could be similarly inactivated by a specific ligand class including the prototypical opioid, morphine. Acute analgesic tolerance to morphine and related opioids (morphine-6-glucuronide and buprenorphine) was blocked by JNK inhibition, but not by G protein receptor kinase 3 knockout. In contrast, a second class of \u03bc-opioids including fentanyl, methadone, and oxycodone produced acute analgesic tolerance that was blocked by G protein receptor kinase 3 knockout, but not by JNK inhibition. Acute MOR desensitization, demonstrated by reduced D-Ala\n                    <jats:sup>2<\/jats:sup>\n                    -Met\n                    <jats:sup>5<\/jats:sup>\n                    -Glyol-enkephalin\u2013stimulated [\n                    <jats:sup>35<\/jats:sup>\n                    S]GTP\u03b3S binding to spinal cord membranes from morphine-pretreated mice, was also blocked by JNK inhibition; however, desensitization of D-Ala\n                    <jats:sup>2<\/jats:sup>\n                    -Met\n                    <jats:sup>5<\/jats:sup>\n                    -Glyol-enkephalin\u2013stimulated [\n                    <jats:sup>35<\/jats:sup>\n                    S]GTP\u03b3S binding following fentanyl pretreatment was not blocked by JNK inhibition. JNK-mediated receptor inactivation of the \u03ba-opioid receptor was evident in both agonist-stimulated [\n                    <jats:sup>35<\/jats:sup>\n                    S]GTP\u03b3S binding and opioid analgesic assays; however, gene knockout of JNK 1 selectively blocked \u03ba-receptor inactivation, whereas deletion of JNK 2 selectively blocked MOR inactivation. These findings suggest that ligand-directed activation of JNK kinases may generally provides an alternate mode of G protein\u2013coupled receptor regulation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1000751107","type":"journal-article","created":{"date-parts":[[2010,6,3]],"date-time":"2010-06-03T22:55:52Z","timestamp":1275605752000},"page":"11608-11613","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":143,"title":["Ligand-directed c-Jun N-terminal kinase activation disrupts opioid receptor signaling"],"prefix":"10.1073","volume":"107","author":[{"given":"Erica J.","family":"Melief","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayumi","family":"Miyatake","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Bruchas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Chavkin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,6,3]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.54.1.94"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M708118200"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.107.043893"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.104463"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.107.040352"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M705540200"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)80032-5"},{"key":"e_1_3_3_8_2","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1016\/S0022-3565(25)11434-1","article-title":"Extremely long-lasting antagonistic actions of nor-binaltorphimine (nor-BNI) in the mouse tail-flick test","volume":"260","author":"Horan P","year":"1992","unstructured":"P Horan, J Taylor, HI Yamamura, F Porreca, Extremely long-lasting antagonistic actions of nor-binaltorphimine (nor-BNI) in the mouse tail-flick test. 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