Ligand‐specific recycling profiles determine distinct potential for chronic analgesic tolerance of delta‐opioid receptor (DOPr) agonists

δ‐opioid receptor (DOPr) agonists have analgesic efficacy in chronic pain models but development of tolerance limits their use for long‐term pain management. 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‐defined. In a rat model of streptozotocin (STZ)‐induced diabetic neuropathy, deltorphin II and TIPP produced sustained analgesia following daily (intrathecal) i.t. injections over six days, whereas similar treatment with SNC‐80 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‐induced sequestration and development of chronic tolerance. Instead, ligands that supported DOPr recycling were also the ones producing sustained analgesia over 6‐day treatment. Moreover, endosomal endothelin‐converting 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.