Considerable effort has recently been directed at developing multifunctional opioid drugs to minimize the unwanted side-effects of opioid analgesics. We developed a novel multifunctional agonist named DN-9. Here, we studied the analgesic profiles and related side-effects of peripheral DN-9 in various pain models.Antinociceptive effects of DN-9 were investigated in nociceptive, inflammatory and neuropathic pain. Whole-cell patch-clamp and calcium imaging assays were used to evaluate the inhibitory effects of DN-9 to calcium current and high-K -induced intracellular calcium ([Ca ] ) on dorsal root ganglion (DRG) neurons, respectively. Furthermore, the side-effects of DN-9 were evaluated in antinociceptive tolerance, abuse, gastrointestinal transit and rotarod tests.Our study showed that subcutaneous DN-9 dose-dependently produced antinociception via peripheral opioid receptors in different pain models without sex difference. In addition, DN-9 exhibited more potent ability than morphine to inhibit calcium current and high-K -induced [Ca ] in DRG neurons. Repeated treatment with DN-9 produced equivalent antinociception for 8 days in multiple pain models, and DN-9 also maintained potent analgesia in morphine-tolerant mice. Furthermore, chronic DN-9 administration had no apparent effect on the microglial activation of spinal cord. DN-9 exhibited less abuse potential compared with morphine after subcutaneous injection, as was gastroparesis and effects on motor coordination.DN-9 produces potent analgesia with minimal side-effects, which strengthen the candidacy of peripherally acting opioids with multifunctional agonistic properties to enter human studies to alleviate the current highly problematic mis-use of classic opioid on a large scale.