BACKGROUND AND PURPOSE A recently discovered multi-target opioid/neuropeptide FF (NPFF) receptor agonist, DN-9, exhibited peripherally acting analgesia. To improve its metabolic stability and blood-brain barrier penetration, we designed and synthesized a novel cyclic disulfide analogue of DN-9, OFP011, and examined its bioactivity using in vitro cAMP and in vivo behavioral experiments. EXPERIMENTAL APPROACH OFP011 was pharmacologically characterized using the in vitro cAMP assays at opioid and NPFF receptors. The blood-brain barrier (BBB) transport property of OFP011 was investigated using pharmacokinetic and pharmacological experiments. Antinociceptive properties of OFP011 were investigated in acute, inflammatory and neuropathic pain. Its adverse effects on locomotor coordination, gastrointestinal transit, antinociceptive tolerance, addiction, reward, and respiration were further assessed. KEY RESULTS OFP011 exhibited multifunctional agonistic efficacies at mu-, delta-, kappa-opioid, NPFF1 and NPFF2 receptors in vitro. The pharmacokinetic and pharmacological experiments demonstrated its BBB permeability after systemic administration. In addition, subcutaneous OFP011 produced potent and long-lasting antinociception via central opioid receptors in various pain models. At the highest analgesic doses, subcutaneous OFP011 induced reduced adverse effects, including tolerance, gastrointestinal transit, motor function, addiction, reward, and respiration depression. Notably, OFP011 achieved oral antinociceptive activity in different pain models. CONCLUSION AND IMPLICATIONS OFP011 exhibited potent and sustained analgesia without opioid-like side effects. Collectively, the results imply that the multifunctional opioid/NPFF receptor agonists with improved BBB penetration may be a promising strategy to treatment of moderate to severe nociceptive and pathological pain with fewer side effects.