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RF313, an orally bioavailable neuropeptide FF receptor antagonist, opposes effects of RF-amide-related peptide-3 and opioid-induced hyperalgesia in rodents.
Neuropharmacology. 2017 05 15; 118:188-198.N

Abstract

Although opiates represent the most effective analgesics, their use in chronic treatments is associated with numerous side effects including the development of pain hypersensitivity and analgesic tolerance. We recently identified a novel orally active neuropeptide FF (NPFF) receptor antagonist, RF313, which efficiently prevents the development of fentanyl-induced hyperalgesia in rats. In this study, we investigated the properties of this compound into more details. We show that RF313 exhibited a pronounced selectivity for NPFF receptors, antagonist activity at NPFF1 receptor (NPFF1R) subtype both in vitro and in vivo and no major side effects when administered in mice up to 30 mg/kg. When co-administered with opiates in rats and mice, it improved their analgesic efficacy and prevented the development of long lasting opioid-induced hyperalgesia. Moreover, and in marked contrast with the dipeptidic NPFF receptor antagonist RF9, RF313 displayed negligible affinity and no agonist activity (up to 100 μM) toward the kisspeptin receptor. Finally, in male hamster, RF313 had no effect when administered alone but fully blocked the increase in LH induced by RFRP-3, while RF9 per se induced a significant increase in LH levels which is consistent with its ability to activate kisspeptin receptors. Altogether, our data indicate that RF313 represents an interesting compound for the development of therapeutic tools aiming at improving analgesic action of opiates and reducing adverse side effects associated with their chronic administration. Moreover, its lack of agonist activity at the kisspeptin receptor indicates that RF313 might be considered a better pharmacological tool, when compared to RF9, to examine the regulatory roles of RF-amide-related peptides and NPFF1R in reproduction.

Authors+Show Affiliations

Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: elhabazi@unistra.fr.Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: jeanpaul.humbert@aol.fr.Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: bertin.i@free.fr.Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: rquillet@unistra.fr.Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: Valerie.Utard@unistra.fr.Laboratoire Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: schneiders@unistra.fr.Laboratoire Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: mschmitt@unistra.fr.Laboratoire Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: jjb@unistra.fr.Homéostasie-Allostasie-Pathologie-Réhabilitation, UMR 5287 CNRS, Université de Bordeaux Segalen, Bordeaux, France. Electronic address: laboureyrasemilie@yahoo.fr.Homéostasie-Allostasie-Pathologie-Réhabilitation, UMR 5287 CNRS, Université de Bordeaux Segalen, Bordeaux, France. Electronic address: mericbb@hotmail.fr.Homéostasie-Allostasie-Pathologie-Réhabilitation, UMR 5287 CNRS, Université de Bordeaux Segalen, Bordeaux, France. Electronic address: gsimonnet@yahoo.com.Institut des Neurosciences Cellulaires et Intégratives, UPR 3212 CNRS, Strasbourg, France. Electronic address: caroline.ancel@gmail.com.Institut des Neurosciences Cellulaires et Intégratives, UPR 3212 CNRS, Strasbourg, France. Electronic address: simonneaux@inci-cnrs.unistra.fr.Physiologie de la Reproduction et des Comportements, INRA, UMR7247 CNRS, Université de Tours, Nouzilly, France. Electronic address: Massimiliano.beltramo@tours.inra.fr.Laboratoire Biophotonique et Pharmacologie, UMR 7213 CNRS, Université de Strasbourg, Illkirch, France. Electronic address: bernard.bucher67@orange.fr.CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), 1 rue Laurent Fries, F-67404 Illkirch-Graffenstaden, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France. Electronic address: tsorg@igbmc.fr.CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), 1 rue Laurent Fries, F-67404 Illkirch-Graffenstaden, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France. Electronic address: meziane@igbmc.fr.CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), 1 rue Laurent Fries, F-67404 Illkirch-Graffenstaden, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France. Electronic address: elodie.schneider@epfl.ch.CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), 1 rue Laurent Fries, F-67404 Illkirch-Graffenstaden, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France. Electronic address: petitd@igbmc.fr.Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: brigitte.ilien@unistra.fr.Laboratoire Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: fbihel@unistra.fr.Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: simonin@unistra.fr.

Pub Type(s)

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

Language

eng

PubMed ID

28288815

Citation

Elhabazi, Khadija, et al. "RF313, an Orally Bioavailable Neuropeptide FF Receptor Antagonist, Opposes Effects of RF-amide-related Peptide-3 and Opioid-induced Hyperalgesia in Rodents." Neuropharmacology, vol. 118, 2017, pp. 188-198.
Elhabazi K, Humbert JP, Bertin I, et al. RF313, an orally bioavailable neuropeptide FF receptor antagonist, opposes effects of RF-amide-related peptide-3 and opioid-induced hyperalgesia in rodents. Neuropharmacology. 2017;118:188-198.
Elhabazi, K., Humbert, J. P., Bertin, I., Quillet, R., Utard, V., Schneider, S., Schmitt, M., Bourguignon, J. J., Laboureyras, E., Ben Boujema, M., Simonnet, G., Ancel, C., Simonneaux, V., Beltramo, M., Bucher, B., Sorg, T., Meziane, H., Schneider, E., Petit-Demoulière, B., ... Simonin, F. (2017). RF313, an orally bioavailable neuropeptide FF receptor antagonist, opposes effects of RF-amide-related peptide-3 and opioid-induced hyperalgesia in rodents. Neuropharmacology, 118, 188-198. https://doi.org/10.1016/j.neuropharm.2017.03.012
Elhabazi K, et al. RF313, an Orally Bioavailable Neuropeptide FF Receptor Antagonist, Opposes Effects of RF-amide-related Peptide-3 and Opioid-induced Hyperalgesia in Rodents. Neuropharmacology. 2017 05 15;118:188-198. PubMed PMID: 28288815.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RF313, an orally bioavailable neuropeptide FF receptor antagonist, opposes effects of RF-amide-related peptide-3 and opioid-induced hyperalgesia in rodents. AU - Elhabazi,Khadija, AU - Humbert,Jean-Paul, AU - Bertin,Isabelle, AU - Quillet,Raphaelle, AU - Utard,Valérie, AU - Schneider,Séverine, AU - Schmitt,Martine, AU - Bourguignon,Jean-Jacques, AU - Laboureyras,Emilie, AU - Ben Boujema,Meric, AU - Simonnet,Guy, AU - Ancel,Caroline, AU - Simonneaux,Valérie, AU - Beltramo,Massimiliano, AU - Bucher,Bernard, AU - Sorg,Tania, AU - Meziane,Hamid, AU - Schneider,Elodie, AU - Petit-Demoulière,Benoit, AU - Ilien,Brigitte, AU - Bihel,Frédéric, AU - Simonin,Frédéric, Y1 - 2017/03/10/ PY - 2016/11/21/received PY - 2017/02/27/revised PY - 2017/03/06/accepted PY - 2017/3/16/pubmed PY - 2017/9/7/medline PY - 2017/3/15/entrez KW - LH secretion KW - Morphine analgesia KW - NPFF receptors KW - Nociception KW - Opioid-induced hyperalgesia KW - RF-amide peptides SP - 188 EP - 198 JF - Neuropharmacology JO - Neuropharmacology VL - 118 N2 - Although opiates represent the most effective analgesics, their use in chronic treatments is associated with numerous side effects including the development of pain hypersensitivity and analgesic tolerance. We recently identified a novel orally active neuropeptide FF (NPFF) receptor antagonist, RF313, which efficiently prevents the development of fentanyl-induced hyperalgesia in rats. In this study, we investigated the properties of this compound into more details. We show that RF313 exhibited a pronounced selectivity for NPFF receptors, antagonist activity at NPFF1 receptor (NPFF1R) subtype both in vitro and in vivo and no major side effects when administered in mice up to 30 mg/kg. When co-administered with opiates in rats and mice, it improved their analgesic efficacy and prevented the development of long lasting opioid-induced hyperalgesia. Moreover, and in marked contrast with the dipeptidic NPFF receptor antagonist RF9, RF313 displayed negligible affinity and no agonist activity (up to 100 μM) toward the kisspeptin receptor. Finally, in male hamster, RF313 had no effect when administered alone but fully blocked the increase in LH induced by RFRP-3, while RF9 per se induced a significant increase in LH levels which is consistent with its ability to activate kisspeptin receptors. Altogether, our data indicate that RF313 represents an interesting compound for the development of therapeutic tools aiming at improving analgesic action of opiates and reducing adverse side effects associated with their chronic administration. Moreover, its lack of agonist activity at the kisspeptin receptor indicates that RF313 might be considered a better pharmacological tool, when compared to RF9, to examine the regulatory roles of RF-amide-related peptides and NPFF1R in reproduction. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/28288815/RF313_an_orally_bioavailable_neuropeptide_FF_receptor_antagonist_opposes_effects_of_RF_amide_related_peptide_3_and_opioid_induced_hyperalgesia_in_rodents_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(17)30095-3 DB - PRIME DP - Unbound Medicine ER -