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Although agonist potential for inducing acute analgesic tolerance has been associated with distinct patterns of DOPr internalization, the association between trafficking and chronic tolerance remains ill\u2010defined. In a rat model of streptozotocin (STZ)\u2010induced diabetic neuropathy, deltorphin II and TIPP produced sustained\u00a0analgesia\u00a0 following daily (intrathecal) i.t. injections over six days, whereas similar treatment with SNC\u201080 or SB235863 led to progressive tolerance and loss of the analgesic response. Trafficking assays in murine neuron cultures showed no association between the magnitude of ligand\u2010induced sequestration and development of chronic tolerance. Instead, ligands that supported DOPr recycling were also the ones producing sustained analgesia over 6\u2010day treatment. Moreover, endosomal endothelin\u2010converting enzyme 2 (ECE2) blocker 663444 prevented DOPr recycling by deltorphin II and TIPP and precipitated tolerance by these ligands. In conclusion, agonists, which support DOPr recycling, avoid development of analgesic tolerance over repeated administration.<\/jats:p>","DOI":"10.1111\/jcmm.15234","type":"journal-article","created":{"date-parts":[[2020,4,12]],"date-time":"2020-04-12T23:14:24Z","timestamp":1586733264000},"page":"5718-5730","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Ligand\u2010specific recycling profiles determine distinct potential for chronic analgesic tolerance of delta\u2010opioid receptor (DOPr) agonists"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1666-2650","authenticated-orcid":false,"given":"Hanieh","family":"Bagheri Tudashki","sequence":"first","affiliation":[{"name":"Centre de Recherche Centre Hospitalier Universitaire Ste-Justine Montr\u00e9al QC 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