title: Endogenous mammalian RF-amide peptides, including PrRP, kisspeptin and 26RFa, modulate nociception and morphine analgesia via NPFF receptors.
abstract: Mammalian RF-amide peptides are encoded by five different genes and act through five different G protein-coupled receptors. RF-amide-related peptides-1 and -3, neuropeptides AF and FF, Prolactin releasing peptides, Kisspeptins and RFa peptides are currently considered endogenous peptides for NPFF1, NPFF2, GPR10, GPR54 and GPR103 receptors, respectively. However, several studies suggest that the selectivity of these peptides for their receptors is low and indicate that expression patterns for receptors and their corresponding ligands only partially overlap. In this study, we took advantage of the cloning of the five human RF-amide receptors to systematically examine their affinity for and their activation by all human RF-amide peptides. Binding experiments, performed on membranes from CHO cells expressing GPR10, GPR54 and GPR103 receptors, confirmed their high affinity and remarkable selectivity for their cognate ligands. Conversely, NPFF1 and NPFF2 receptors displayed high affinity for all RF-amide peptides. Moreover, GTPγS and cAMP experiments showed that almost all RF-amide peptides efficiently activate NPFF1 and NPFF2 receptors. As NPFF is known to modulate morphine analgesia, we undertook a systematic analysis in mice of the hyperalgesic and anti morphine-induced analgesic effects of a representative set of endogenous RF-amide peptides. All of them induced hyperalgesia and/or prevented morphine analgesia following intracerebroventricular administration. Importantly, these effects were prevented by administration of RF9, a highly selective NPFF1/NPFF2 antagonist. Altogether, our results show that all endogenous RF-amide peptides display pain-modulating properties and point to NPFF receptors as essential players for these effects.
authors.affiliation: Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Medalis, 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 Medalis, 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 Medalis, Illkirch, France. Electronic address: bertin.i@free.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bertin
authors.affiliation: Laboratoire Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, Laboratory of Excellence Medalis, 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 Medalis, Illkirch, France. Electronic address: fbihel@unistra.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bihel
authors.affiliation: Laboratoire Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, Laboratory of Excellence Medalis, Illkirch, France. Electronic address: jjb@unistra.fr.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Bourguignon
authors.affiliation: Laboratoire Biophotonique et Pharmacologie, UMR 7213 CNRS, Université de Strasbourg, Illkirch, France. Electronic address: bernard.bucher@unistra.fr.
authors.forename: Bernard
authors.initials: B
authors.lastname: Bucher
authors.affiliation: IGBMC, UMR 7104 CNRS, U 964 INSERM, Université de Strasbourg, Illkirch, France. Electronic address: jbecker@igbmc.fr.
authors.forename: Jérôme A J
authors.initials: JA
authors.lastname: Becker
authors.affiliation: Institut Clinique de la Souris, PHENOMIN, IGBMC/ICS-MCI, Université de Strasbourg-CNRS-INSERM, Illkirch, France; PhenoPro, Illkirch, France. Electronic address: tsorg@igbmc.fr.
authors.forename: Tania
authors.initials: T
authors.lastname: Sorg
authors.affiliation: Institut Clinique de la Souris, PHENOMIN, IGBMC/ICS-MCI, Université de Strasbourg-CNRS-INSERM, Illkirch, France. Electronic address: meziane@igbmc.fr.
authors.forename: Hamid
authors.initials: H
authors.lastname: Meziane
authors.affiliation: Institut Clinique de la Souris, PHENOMIN, IGBMC/ICS-MCI, Université de Strasbourg-CNRS-INSERM, Illkirch, France; PhenoPro, 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 Medalis, Illkirch, France. Electronic address: brigitte.ilien@unistra.fr.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Ilien
authors.affiliation: Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Laboratory of Excellence Medalis, Illkirch, France. Electronic address: simonin@unistra.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Simonin
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006801:Humans; D059648:Kisspeptins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects; D056690:Prolactin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D018013:Receptors, Neuropeptide / Q000378:metabolism*; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D000701:Analgesics, Opioid; C106628:KISS1 protein, human; D059648:Kisspeptins; D009479:Neuropeptides; C534377:PRLH protein, human; D056690:Prolactin-Releasing Hormone; D018013:Receptors, Neuropeptide; C083929:neuropeptide FF receptor; C480638:prepro-26RFa protein, human; D014316:Tritium; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine; D000242:Cyclic AMP; D002118:Calcium
keywords: AUC; GPR10; GPR103; GPR54; Kp; NPAF; NPFF; NPFF receptors; NPSF; NPVF; Nociception and morphine analgesia; PrRP; RF-amide peptides; RF-amide-related peptide; RFRP; area-under-the-curve; i.c.v.; i.t.; intracerebroventricular; intrathecal; kisspeptin; neuropeptide AF; neuropeptide FF; neuropeptide SF; neuropeptide VF; prolactin releasing peptide