RF313, an orally bioavailable neuropeptide FF receptor antagonist, opposes effects of RF-amide-related peptide-3 and opioid-induced hyperalgesia in rodents

NEUROPHARMACOLOGY

卷:118

Article

Elhabazi, Khadija¹  Humbert, Jean-Paul¹  Bertin, Isabelle¹  Quillet, Raphaelle¹  Utard, Valerie¹  Schneider, Severine²  Schmitt, Martine²  Bourguignon, Jean-Jacques²  Laboureyras, Emilie³  Ben Boujema, Meric³  Simonnet, Guy³  Ancel, Caroline⁴  Simonneaux, Valerie⁴  Beltramo, Massimiliano⁵  Bucher, Bernard⁶  Sorg, Tania^7,8,9,10  Meziane, Hamid^7,8,9,10  Schneider, Elodie^7,8,9,10  Petit-Demouliere, Benoit^7,8,9,10  Ilien, Brigitte¹  Simonin, Frederic¹ 

[1] Univ Strasbourg, UMR CNRS 7242, Lab Excellence Medalis, Biotechnol & Signalisat Cellulaire, Illkirch Graffenstaden, France

[2] Univ Strasbourg, UMR CNRS 7200, Lab Innovat Therapeut, Lab Excellence Medalis, Illkirch Graffenstaden, France

[3] Univ Bordeaux Segalen, UMR CNRS 5287, Homeostasie Allostasie Pathol Rehabil, Bordeaux, France

[4] CNRS, UPR 3212, Inst Neurosci Cellulaires & Integrat, Strasbourg, France

[5] Univ Tours, INRA, Physiol Reprod & Comportements, Nouzilly, France

[6] Univ Strasbourg, UMR CNRS 7213, Lab Biophoton & Pharmacol, Illkirch Graffenstaden, France

[7] Inst Clin Souris, CELPHEDIA, PHENOMIN, 1 Rue Laurent Fries, F-67404 Illkirch Graffenstaden, France

[8] Univ Strasbourg, Inst Genet & Biol Mol & Cellulaire, 1 Rue Laurent Fries, F-67404 Illkirch Graffenstaden, France

[9] CNRS, UMR7104, Illkirch Graffenstaden, France

[10] Inst Natl Sante & Rech Med, U964, Illkirch Graffenstaden, France

关键词: NPFF receptors;    RF-amide peptides;    Nociception;    Morphine analgesia;    Opioid-induced hyperalgesia;    LH secretion;   

DOI  :  10.1016/j.neuropharm.2017.03.012

来源: Elsevier

【 摘 要 】

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 mu M) 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. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

Free