title: 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.affiliation: Inserm, UMR-S 1144, Paris, France.|Paris-Descartes University, UMR-S 1144, Paris, France.|Paris-Diderot University, UMR-S 1144, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Lagard
authors.affiliation: Inserm, UMR-S 1144, Paris, France.|Paris-Descartes University, UMR-S 1144, Paris, France.|Paris-Diderot University, UMR-S 1144, Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Chevillard
authors.affiliation: Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Guillemyn
authors.affiliation: Inserm, UMR-S 1144, Paris, France.|Paris-Descartes University, UMR-S 1144, Paris, France.|Paris-Diderot University, UMR-S 1144, Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Risède
authors.affiliation: Inserm, UMR-S 1144, Paris, France.|Paris-Descartes University, UMR-S 1144, Paris, France.|Paris-Diderot University, UMR-S 1144, Paris, France.|Assistance Publique-Hôpitaux de Paris, Lariboisière Hospital, Laboratory of Biochemistry and Molecular Biology, Paris, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Laplanche
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria.
authors.forename: Mariana
authors.initials: M
authors.lastname: Spetea
authors.affiliation: Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Ballet
authors.affiliation: Inserm, UMR-S 1144, Paris, France.|Paris-Descartes University, UMR-S 1144, Paris, France.|Paris-Diderot University, UMR-S 1144, Paris, France.|Assistance Publique-Hôpitaux de Paris, Lariboisière Hospital, Department of Medical and Toxicological Critical Care, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Mégarbane
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy; D007211:Indoles / Q000627:therapeutic use; D008024:Ligands; D008297:Male; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D009437:Neuralgia / Q000188:drug therapy*; D059226:Nociceptive Pain / Q000188:drug therapy*; D009842:Oligopeptides / Q000737:chemistry / Q000627:therapeutic use; D018847:Opioid Peptides / Q000037:antagonists & inhibitors*; D010147:Pain Measurement; D010455:Peptides / Q000627:therapeutic use*; D043803:Phenalenes / Q000627:therapeutic use; D010991:Plethysmography; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid; D012119:Respiration / Q000187:drug effects; D013997:Time Factors; D014147:Tramadol / Q000627:therapeutic use; D000097629:Nociceptin
chemical_list: D000701:Analgesics, Opioid; D007211:Indoles; D008024:Ligands; D009292:Narcotic Antagonists; D009842:Oligopeptides; D018847:Opioid Peptides; D010455:Peptides; D043803:Phenalenes; D011957:Receptors, Opioid; D014147:Tramadol; D000097629:Nociceptin; C583123:1-(1-(2,3,3alpha,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)indolin-2-one; C000624685:KGNOP1 peptide; C000624686:KGNOP3 peptide