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Bifunctional peptide-based opioid agonist/nociceptin antagonist ligand for dual treatment of nociceptive and neuropathic pain.
Pain. 2017 03; 158(3):505-515.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+Show Affiliations

Inserm, UMR-S 1144, Paris, France. Paris-Descartes University, UMR-S 1144, Paris, France. Paris-Diderot University, UMR-S 1144, Paris, France.Inserm, UMR-S 1144, Paris, France. Paris-Descartes University, UMR-S 1144, Paris, France. Paris-Diderot University, UMR-S 1144, Paris, France.Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium.Inserm, UMR-S 1144, Paris, France. Paris-Descartes University, UMR-S 1144, Paris, France. Paris-Diderot University, UMR-S 1144, Paris, France.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.Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria.Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28135212

Citation

Lagard, Camille, et al. "Bifunctional Peptide-based Opioid Agonist/nociceptin Antagonist Ligand for Dual Treatment of Nociceptive and Neuropathic Pain." Pain, vol. 158, no. 3, 2017, pp. 505-515.
Lagard C, Chevillard L, Guillemyn K, et al. Bifunctional peptide-based opioid agonist/nociceptin antagonist ligand for dual treatment of nociceptive and neuropathic pain. Pain. 2017;158(3):505-515.
Lagard, C., Chevillard, L., Guillemyn, K., Risède, P., Laplanche, J. L., Spetea, M., Ballet, S., & Mégarbane, B. (2017). Bifunctional peptide-based opioid agonist/nociceptin antagonist ligand for dual treatment of nociceptive and neuropathic pain. Pain, 158(3), 505-515. https://doi.org/10.1097/j.pain.0000000000000790
Lagard C, et al. Bifunctional Peptide-based Opioid Agonist/nociceptin Antagonist Ligand for Dual Treatment of Nociceptive and Neuropathic Pain. Pain. 2017;158(3):505-515. PubMed PMID: 28135212.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bifunctional peptide-based opioid agonist/nociceptin antagonist ligand for dual treatment of nociceptive and neuropathic pain. AU - Lagard,Camille, AU - Chevillard,Lucie, AU - Guillemyn,Karel, AU - Risède,Patricia, AU - Laplanche,Jean-Louis, AU - Spetea,Mariana, AU - Ballet,Steven, AU - Mégarbane,Bruno, PY - 2017/1/31/pubmed PY - 2017/11/29/medline PY - 2017/1/31/entrez SP - 505 EP - 515 JF - Pain JO - Pain VL - 158 IS - 3 N2 - 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. SN - 1872-6623 UR - https://www.unboundmedicine.com/medline/citation/28135212/Bifunctional_peptide_based_opioid_agonist/nociceptin_antagonist_ligand_for_dual_treatment_of_nociceptive_and_neuropathic_pain_ L2 - https://doi.org/10.1097/j.pain.0000000000000790 DB - PRIME DP - Unbound Medicine ER -