title: RF313, an orally bioavailable neuropeptide FF receptor antagonist, opposes effects of RF-amide-related peptide-3 and opioid-induced hyperalgesia in rodents.
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.affiliation: Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: elhabazi@unistra.fr.
authors.forename: Khadija
authors.initials: K
authors.lastname: Elhabazi
authors.affiliation: Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: jeanpaul.humbert@aol.fr.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Humbert
authors.affiliation: Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: bertin.i@free.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bertin
authors.affiliation: Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: rquillet@unistra.fr.
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Quillet
authors.affiliation: Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: Valerie.Utard@unistra.fr.
authors.forename: Valérie
authors.initials: V
authors.lastname: Utard
authors.affiliation: Laboratoire Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: schneiders@unistra.fr.
authors.forename: Séverine
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Laboratoire Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: mschmitt@unistra.fr.
authors.forename: Martine
authors.initials: M
authors.lastname: Schmitt
authors.affiliation: Laboratoire Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: jjb@unistra.fr.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Bourguignon
authors.affiliation: Homéostasie-Allostasie-Pathologie-Réhabilitation, UMR 5287 CNRS, Université de Bordeaux Segalen, Bordeaux, France. Electronic address: laboureyrasemilie@yahoo.fr.
authors.forename: Emilie
authors.initials: E
authors.lastname: Laboureyras
authors.affiliation: Homéostasie-Allostasie-Pathologie-Réhabilitation, UMR 5287 CNRS, Université de Bordeaux Segalen, Bordeaux, France. Electronic address: mericbb@hotmail.fr.
authors.forename: Meric
authors.initials: M
authors.lastname: Ben Boujema
authors.affiliation: Homéostasie-Allostasie-Pathologie-Réhabilitation, UMR 5287 CNRS, Université de Bordeaux Segalen, Bordeaux, France. Electronic address: gsimonnet@yahoo.com.
authors.forename: Guy
authors.initials: G
authors.lastname: Simonnet
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, UPR 3212 CNRS, Strasbourg, France. Electronic address: caroline.ancel@gmail.com.
authors.forename: Caroline
authors.initials: C
authors.lastname: Ancel
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, UPR 3212 CNRS, Strasbourg, France. Electronic address: simonneaux@inci-cnrs.unistra.fr.
authors.forename: Valérie
authors.initials: V
authors.lastname: Simonneaux
authors.affiliation: Physiologie de la Reproduction et des Comportements, INRA, UMR7247 CNRS, Université de Tours, Nouzilly, France. Electronic address: Massimiliano.beltramo@tours.inra.fr.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Beltramo
authors.affiliation: Laboratoire Biophotonique et Pharmacologie, UMR 7213 CNRS, Université de Strasbourg, Illkirch, France. Electronic address: bernard.bucher67@orange.fr.
authors.forename: Bernard
authors.initials: B
authors.lastname: Bucher
authors.affiliation: 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.
authors.forename: Tania
authors.initials: T
authors.lastname: Sorg
authors.affiliation: 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.
authors.forename: Hamid
authors.initials: H
authors.lastname: Meziane
authors.affiliation: 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.
authors.forename: Elodie
authors.initials: E
authors.lastname: Schneider
authors.affiliation: 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.
authors.forename: Benoit
authors.initials: B
authors.lastname: Petit-Demoulière
authors.affiliation: Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: brigitte.ilien@unistra.fr.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Ilien
authors.affiliation: Laboratoire Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: fbihel@unistra.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bihel
authors.affiliation: Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Médalis, Illkirch, France. Electronic address: simonin@unistra.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Simonin
mesh_terms: D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D005283:Fentanyl / Q000494:pharmacology; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D009842:Oligopeptides / Q000737:chemistry / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use; D010880:Piperidines / Q000737:chemistry / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009842:Oligopeptides; D010455:Peptides; D010880:Piperidines; C000622195:RF313 compound; D018013:Receptors, Neuropeptide; C083929:neuropeptide FF receptor; C053651:phenylalanyl-leucyl-phenylalanyl-glutaminyl-prolyl-glutaminyl-arginyl-phenylalaninamide; D014633:Valine; D005283:Fentanyl
keywords: LH secretion; Morphine analgesia; NPFF receptors; Nociception; Opioid-induced hyperalgesia; RF-amide peptides