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

Abstract

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 (TI) and minute ventilation (VM) 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% (ED50). Pain-related effects on cold hyperalgesia were markedly increased by KGNOP1 as compared to KGNOP3 and tramadol (ED50: 0.0004, 0.32, and 12.1 μmol/kg, respectively), whereas effects on thermal nociception were significantly higher with KGNOP1 as compared to morphine (ED50: 0.41 and 14.7 μmol/kg, respectively). KGNOP1 and KGOP1 produced a larger increase in TI and deleterious decrease in VM in comparison to morphine and tramadol (ED50(TI): 0.63, 0.52, 12.2, and 50.9 μmol/kg; ED50(VM): 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 (ED50 ratio: 5.44 × 10 vs 0.24) and morphine (ED50 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.

• Authors: Camille Lagard, Lucie Chevillard, Karel Guillemyn, Patricia Risède, Jean-Louis Laplanche, Mariana Spetea, Steven Ballet, Bruno Mégarbane
• Journal: Pain (Pain) Vol. 158 Issue 3 Pg. 505-515 (03 2017) ISSN: 1872-6623 [Electronic] United States
• PMID: 28135212 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(1-(2,3,3alpha,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)indolin-2-one
• Analgesics, Opioid
• Indoles
• KGNOP1 peptide
• KGNOP3 peptide
• Ligands
• Narcotic Antagonists
• Oligopeptides
• Opioid Peptides
• Peptides
• Phenalenes
• Receptors, Opioid
• Tramadol

Topics

• Analgesics, Opioid (therapeutic use)
• Animals
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Hyperalgesia (drug therapy)
• Indoles (therapeutic use)
• Ligands
• Male
• Narcotic Antagonists (therapeutic use)
• Neuralgia (drug therapy)
• Nociceptive Pain (drug therapy)
• Oligopeptides (chemistry, therapeutic use)
• Opioid Peptides (antagonists & inhibitors)
• Pain Measurement
• Peptides (therapeutic use)
• Phenalenes (therapeutic use)
• Plethysmography
• Rats
• Rats, Sprague-Dawley
• Receptors, Opioid
• Respiration (drug effects)
• Time Factors
• Tramadol (therapeutic use)
• Nociceptin