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Antinociceptive Efficacy of the µ-Opioid/Nociceptin Peptide-Based Hybrid KGNOP1 in Inflammatory Pain without Rewarding Effects in Mice: An Experimental Assessment and Molecular Docking.
Molecules. 2021 05 28; 26(11)M

Abstract

Opioids are the most effective analgesics, with most clinically available opioids being agonists to the µ-opioid receptor (MOR). The MOR is also responsible for their unwanted effects, including reward and opioid misuse leading to the current public health crisis. The imperative need for safer, non-addictive pain therapies drives the search for novel leads and new treatment strategies. In this study, the recently discovered MOR/nociceptin (NOP) receptor peptide hybrid KGNOP1 (H-Dmt-D-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) was evaluated following subcutaneous administration in mouse models of acute (formalin test) and chronic inflammatory pain (Complete Freund's adjuvant-induced paw hyperalgesia), liabilities of spontaneous locomotion, conditioned place preference, and the withdrawal syndrome. KGNOP1 demonstrated dose-dependent antinociceptive effects in the formalin test, and efficacy in attenuating thermal hyperalgesia with prolonged duration of action. Antinociceptive effects of KGNOP1 were reversed by naltrexone and SB-612111, indicating the involvement of both MOR and NOP receptor agonism. In comparison with morphine, KGNOP1 was more potent and effective in mouse models of inflammatory pain. Unlike morphine, KGNOP1 displayed reduced detrimental liabilities, as no locomotor impairment nor rewarding and withdrawal effects were observed. Docking of KGNOP1 to the MOR and NOP receptors and subsequent 3D interaction pattern analyses provided valuable insights into its binding mode. The mixed MOR/NOP receptor peptide KGNOP1 holds promise in the effort to develop new analgesics for the treatment of various pain states with fewer MOR-mediated side effects, particularly abuse and dependence liabilities.

Authors+Show Affiliations

Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, D-14195 Berlin, Germany.Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, D-14195 Berlin, Germany.Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34071603

Citation

Dumitrascuta, Maria, et al. "Antinociceptive Efficacy of the µ-Opioid/Nociceptin Peptide-Based Hybrid KGNOP1 in Inflammatory Pain Without Rewarding Effects in Mice: an Experimental Assessment and Molecular Docking." Molecules (Basel, Switzerland), vol. 26, no. 11, 2021.
Dumitrascuta M, Bermudez M, Trovato O, et al. Antinociceptive Efficacy of the µ-Opioid/Nociceptin Peptide-Based Hybrid KGNOP1 in Inflammatory Pain without Rewarding Effects in Mice: An Experimental Assessment and Molecular Docking. Molecules. 2021;26(11).
Dumitrascuta, M., Bermudez, M., Trovato, O., De Neve, J., Ballet, S., Wolber, G., & Spetea, M. (2021). Antinociceptive Efficacy of the µ-Opioid/Nociceptin Peptide-Based Hybrid KGNOP1 in Inflammatory Pain without Rewarding Effects in Mice: An Experimental Assessment and Molecular Docking. Molecules (Basel, Switzerland), 26(11). https://doi.org/10.3390/molecules26113267
Dumitrascuta M, et al. Antinociceptive Efficacy of the µ-Opioid/Nociceptin Peptide-Based Hybrid KGNOP1 in Inflammatory Pain Without Rewarding Effects in Mice: an Experimental Assessment and Molecular Docking. Molecules. 2021 05 28;26(11) PubMed PMID: 34071603.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antinociceptive Efficacy of the µ-Opioid/Nociceptin Peptide-Based Hybrid KGNOP1 in Inflammatory Pain without Rewarding Effects in Mice: An Experimental Assessment and Molecular Docking. AU - Dumitrascuta,Maria, AU - Bermudez,Marcel, AU - Trovato,Olga, AU - De Neve,Jolien, AU - Ballet,Steven, AU - Wolber,Gerhard, AU - Spetea,Mariana, Y1 - 2021/05/28/ PY - 2021/04/20/received PY - 2021/05/18/revised PY - 2021/05/26/accepted PY - 2021/6/2/entrez PY - 2021/6/3/pubmed PY - 2021/7/24/medline KW - inflammatory pain KW - molecular docking KW - multitarget ligands KW - nociceptin receptor KW - reward KW - side effects KW - µ-opioid receptor JF - Molecules (Basel, Switzerland) JO - Molecules VL - 26 IS - 11 N2 - Opioids are the most effective analgesics, with most clinically available opioids being agonists to the µ-opioid receptor (MOR). The MOR is also responsible for their unwanted effects, including reward and opioid misuse leading to the current public health crisis. The imperative need for safer, non-addictive pain therapies drives the search for novel leads and new treatment strategies. In this study, the recently discovered MOR/nociceptin (NOP) receptor peptide hybrid KGNOP1 (H-Dmt-D-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) was evaluated following subcutaneous administration in mouse models of acute (formalin test) and chronic inflammatory pain (Complete Freund's adjuvant-induced paw hyperalgesia), liabilities of spontaneous locomotion, conditioned place preference, and the withdrawal syndrome. KGNOP1 demonstrated dose-dependent antinociceptive effects in the formalin test, and efficacy in attenuating thermal hyperalgesia with prolonged duration of action. Antinociceptive effects of KGNOP1 were reversed by naltrexone and SB-612111, indicating the involvement of both MOR and NOP receptor agonism. In comparison with morphine, KGNOP1 was more potent and effective in mouse models of inflammatory pain. Unlike morphine, KGNOP1 displayed reduced detrimental liabilities, as no locomotor impairment nor rewarding and withdrawal effects were observed. Docking of KGNOP1 to the MOR and NOP receptors and subsequent 3D interaction pattern analyses provided valuable insights into its binding mode. The mixed MOR/NOP receptor peptide KGNOP1 holds promise in the effort to develop new analgesics for the treatment of various pain states with fewer MOR-mediated side effects, particularly abuse and dependence liabilities. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/34071603/Antinociceptive_Efficacy_of_the_µ_Opioid/Nociceptin_Peptide_Based_Hybrid_KGNOP1_in_Inflammatory_Pain_without_Rewarding_Effects_in_Mice:_An_Experimental_Assessment_and_Molecular_Docking_ L2 - https://www.mdpi.com/resolver?pii=molecules26113267 DB - PRIME DP - Unbound Medicine ER -