Dual-target opioid/neurotensin ligands drive potent and safer analgesia in vivo.

The ongoing opioid crisis underscores the urgent need for safer and more effective analgesics. One promising strategy involves designing bifunctional compounds that engage complementary antinociceptive systems to enhance efficacy while minimizing adverse effects. In this context, the neurotensin (NT) system is particularly attractive, as it produces long-lasting, opioid-independent analgesia and acts synergistically with opioid signaling. Here, we report the in vivo characterization of bifunctional opioid-neurotensin (OPNT) hybrid peptides, in which a dual MOP/DOP agonist is fused to a selective NTS2 agonist. These hybrids retained high affinity for MOP and DOP receptors, selective binding to NTS2 receptors, and partial agonist activity at MOP, a profile associated with reduced opioid-related liabilities. Among the series, SBL-OPNT-13 emerged as the lead compound, producing robust and sustained antinociceptive effects across multiple pain models, including acute thermal nociception, formalin-induced pain, postoperative hypersensitivity, and chronic inflammatory pain. Following intraperitoneal administration, SBL-OPNT-13 outperformed morphine, displaying greater potency and a prolonged duration of action lasting up to 24 h. Importantly, SBL-OPNT-13 was shown to cross the blood-brain barrier, supporting the role of the opioid pharmacophore as a shuttle for brain delivery of the NT moiety. From a safety perspective, SBL-OPNT-13 displayed reduced NTS1-mediated effects, such as hypotension and hypothermia, compared with earlier OPNT hybrids. Although opioid constipation was observed, repeated intrathecal administration resulted in partial tolerance, with a substantial residual antinociceptive effect, potentially reflecting the contribution of the NT pharmacophore. Together, these findings validate the dual-target strategy and identify SBL-OPNT-13 as a promising next-generation analgesic.