Bifunctional peptide-based opioid agonist/nociceptin antagonist ligand for dual treatment of nociceptive and neuropathic pain
| العنوان: | Bifunctional peptide-based opioid agonist/nociceptin antagonist ligand for dual treatment of nociceptive and neuropathic pain |
|---|---|
| المؤلفون: | Camille, Lagard, Lucie, Chevillard, Karel, Guillemyn, Patricia, Risède, Jean-Louis, Laplanche, Mariana, Spetea, Steven, Ballet, Bruno, Mégarbane |
| المساهمون: | Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Vrije Universiteit Brussel (VUB), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Leopold Franzens Universität Innsbruck - University of Innsbruck, Service de réanimation médicale et toxicologique [AP-HP Hôpital Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Chevillard, Lucie |
| المصدر: | PAIN PAIN, 2017, 158 (3), pp.505-515. ⟨10.1097/j.pain.0000000000000790⟩ Pain |
| بيانات النشر: | HAL CCSD, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Male, Indoles, Time Factors, Narcotic Antagonists, Ligands, Neuropathic pain, Nociceptive Pain, Rats, Sprague-Dawley, Animals, Tramadol, Pain Measurement, Dose-Response Relationship, Drug, Morphine, Toxicity, Respiration, food and beverages, Opioid-nociceptin hybrid, Phenalenes, Rats, Analgesics, Opioid, Plethysmography, [SDV.TOX] Life Sciences [q-bio]/Toxicology, Disease Models, Animal, ED50, Opioid Peptides, Hyperalgesia, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Receptors, Opioid, Neuralgia, Respiratory depression, Peptides, Oligopeptides, Research Paper |
| الوصف: | KGNOP1, a mu-opioid receptor agonist/nociceptin receptor antagonist hybrid, can dually treat experimental neuropathic and nociceptive pain, more efficiently and safely than tramadol and morphine, respectively. 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 × 10−3 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. |
| اللغة: | English |
| تدمد: | 0304-3959 1872-6623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::5595615accbe581dac8cbb23488e885c https://hal.science/hal-03822929 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.pmid.dedup....5595615accbe581dac8cbb23488e885c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 03043959 18726623 |
|---|