Bifunctional peptide-based opioid agonist/nociceptin antagonist ligand for dual treatment of nociceptive and neuropathic pain

Drugs able to treat both nociceptive and neuropathic pain effectively without major side effects are lacking. We developed a bifunctional peptide-based hybrid (KGNOP1) that structurally combines a mu-opioid receptor agonist (KGOP1) with antinociceptive activity and a weak nociceptin receptor antagonist (KGNOP3) with anti-neuropathic pain activity. We investigated KGNOP1-related behavioral effects after intravenous administration in rats by assessing thermal nociception, cold hyperalgesia in a model of neuropathic pain induced by chronic constriction injury of the sciatic nerve, and plethysmography parameters including inspiratory time (T(I)) and minute ventilation (V(M)) in comparison to the well-known opioid analgesics, tramadol and morphine. Time-course and dose-dependent effects were investigated for all behavioral parameters to determine the effective doses 50% (ED(50)). Pain-related effects on cold hyperalgesia were markedly increased by KGNOP1 as compared to KGNOP3 and tramadol (ED(50): 0.0004, 0.32, and 12.1 μmol/kg, respectively), whereas effects on thermal nociception were significantly higher with KGNOP1 as compared to morphine (ED(50): 0.41 and 14.7 μmol/kg, respectively). KGNOP1 and KGOP1 produced a larger increase in T(I) and deleterious decrease in V(M) in comparison to morphine and tramadol (ED(50)(T(I)): 0.63, 0.52, 12.2, and 50.9 μmol/kg; ED(50)(V(M)): 0.57, 0.66, 10.6, and 50.0 μmol/kg, respectively). Interestingly, the calculated ratios of anti-neuropathic pain/antinociceptive to respiratory effects revealed that KGNOP1 was safer than tramadol (ED(50) ratio: 5.44 × 10(−3) vs 0.24) and morphine (ED(50) ratio: 0.72 vs 1.39). We conclude that KGNOP1 is able to treat both experimental neuropathic and nociceptive pain, more efficiently and safely than tramadol and morphine, respectively, and thus should be a candidate for future clinical developments.