The Experts below are selected from a list of 534 Experts worldwide ranked by ideXlab platform
Catherine Mollereau - One of the best experts on this subject based on the ideXlab platform.
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Nonpeptide Small Molecule Agonist and Antagonist Original Leads for Neuropeptide
2016Co-Authors: Ff Receptors, Catherine Mollereau, Blair V. Journigan, Neha Vyas, Shainnel O. Eans, Stephen J. Cutler, Jay P. Mclaughlin, Christopher R. MccurdyAbstract:ABSTRACT: Neuropeptide FF1 and FF2 receptors (NPFF1-R and NPFF2-R), and their endogenous ligand NPFF, are one of only several systems responsible for mediating opioid-induced hyperalgesia, tolerance, and dependence. Currently, no small molecules displaying good aFFinity or selectivity for either subtype have been reported, to decipher the role of NPFF2-R as it relates to opioid-mediated analgesia, for further exploration of NPFF1-R, or for medication development for either subtype. We report the first nonpeptide small molecule scaFFold for NPFF1,2-R, the guanidino-piperidines, and SAR studies resulting in the discovery of a NPFF1 agonist (7b, Ki = 487 ± 117 nM), a NPFF1 antagonist (46, Ki = 81 ± 17 nM), and a NPFF2 partial antagonist (53a, Ki = 30 ± 5 nM), which serve as leads for the development of pharmacological probes and potential therapeutic agents. Testing of 46 alone was without eFFect in the mouse 48 °C warm-water tail-withdrawal test, but pretreatment with 46 prevented NPFF-induced hyperalgesia. The Neuropeptide FF (NPFF) system comprises two receptor subtypes, NPFF1 and NPFF2 receptors (NPFF1-R and NPFF2-R), which are Gi/o coupled G-protein coupled receptors (GPCRs) with 30−35 % homology to Neuropeptide Y an
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mimicking of arginine by functionalized nω carbamoylated arginine as a new broadly applicable approach to labeled bioactive peptides high aFFinity angiotensin Neuropeptide y Neuropeptide FF and neurotensin receptor ligands as examples
Journal of Medicinal Chemistry, 2016Co-Authors: Max Keller, Kilian K Kuhn, Jurgen Einsiedel, Harald Hubner, Sabrina Biselli, Catherine Mollereau, David Wifling, Jaroslava Svobodova, Gunther Bernhardt, Chiara CabreleAbstract:Derivatization of biologically active peptides by conjugation with fluorophores or radionuclide-bearing moieties is an eFFective and commonly used approach to prepare molecular tools and diagnostic agents. Whereas lysine, cysteine, and N-terminal amino acids have been mostly used for peptide conjugation, we describe a new, widely applicable approach to peptide conjugation based on the nonclassical bioisosteric replacement of the guanidine group in arginine by a functionalized carbamoylguanidine moiety. Four arginine-containing peptide receptor ligands (angiotensin II, neurotensin(8–13), an analogue of the C-terminal pentapeptide of Neuropeptide Y, and a Neuropeptide FF analogue) were subject of this proof-of-concept study. The Nω-carbamoylated arginines, bearing spacers with a terminal amino group, were incorporated into the peptides by standard Fmoc solid phase peptide synthesis. The synthesized chemically stable peptide derivatives showed high receptor aFFinities with Ki values in the low nanomolar rang...
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Mimicking of Arginine by Functionalized Nω‑Carbamoylated Arginine As a New Broadly Applicable Approach to Labeled Bioactive Peptides: High AFFinity Angiotensin, Neuropeptide Y, Neuropeptide FF, and Neurotensin Receptor Ligands As Examples
2016Co-Authors: Max Keller, Jurgen Einsiedel, Sabrina Biselli, Catherine Mollereau, David Wifling, Kilian K. Kuhn, Harald Hübner, Jaroslava Svobodová, Günther Bernhardt, Chiara CabreleAbstract:Derivatization of biologically active peptides by conjugation with fluorophores or radionuclide-bearing moieties is an eFFective and commonly used approach to prepare molecular tools and diagnostic agents. Whereas lysine, cysteine, and N-terminal amino acids have been mostly used for peptide conjugation, we describe a new, widely applicable approach to peptide conjugation based on the nonclassical bioisosteric replacement of the guanidine group in arginine by a functionalized carbamoylguanidine moiety. Four arginine-containing peptide receptor ligands (angiotensin II, neurotensin(8–13), an analogue of the C-terminal pentapeptide of Neuropeptide Y, and a Neuropeptide FF analogue) were subject of this proof-of-concept study. The Nω-carbamoylated arginines, bearing spacers with a terminal amino group, were incorporated into the peptides by standard Fmoc solid phase peptide synthesis. The synthesized chemically stable peptide derivatives showed high receptor aFFinities with Ki values in the low nanomolar range, even when bulky fluorophores had been attached. Two new tritiated tracers for angiotensin and neurotensin receptors are described
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Development of a Peptidomimetic Antagonist of Neuropeptide FF Receptors for the Prevention of Opioid-Induced Hyperalgesia
2015Co-Authors: Frédéric Bihel, Martine Schmitt, Isabelle Bertin, Emilie Laboureyras, Jean-paul Humbert, Séverine Schneider, Patrick Wagner, Benoît Petit-demoulière, Elodie Schneider, Catherine MollereauAbstract:Through the development of a new class of unnatural ornithine derivatives as bioisosteres of arginine, we have designed an orally active peptidomimetic antagonist of Neuropeptide FF receptors (NPFFR). Systemic low-dose administration of this compound to rats blocked opioid-induced hyperalgesia, without any apparent side-eFFects. Interestingly, we also observed that this compound potentiated opioid-induced analgesia. This unnatural ornithine derivative provides a novel therapeutic approach for both improving analgesia and reducing hyperalgesia induced by opioids in patients being treated for chronic pain
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currents in a dorsal root ganglion cell line
2013Co-Authors: Short Communication, Catherine Mollereau, Michel Roumy, Jeanmarie ZajacAbstract:This study investigated the presence of Neuropeptide FF (NPFF) receptors on F-11 cells, a hybridoma derived from rat dorsal root ganglia (DRG) and mouse neuroblastoma. Binding experiments revealed a low density (4 fmol/mg) of high aFFinity (0.5 nM) [ 3 H]-EYF binding sites in these cells. The whole-cell planar patch-clamp technique showed that dNPA, a selective NPFF2 agonist, increased the voltage-dependent potassium outward currents (about 30 pA/pF) by 21%; this reversible eFFect on sustained delayed potassium currents is blocked by tetraethylammonium. The similar eFFects of NPFF and opioid agonists on K + currents in this cell line may explain their similar antinociceptive actions at the spinal level. Key words: Neuropeptide FF, receptor, neuroblastoma F-11 cell, K + current, opioi
Jeanmarie Zajac - One of the best experts on this subject based on the ideXlab platform.
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Neuropeptide FF/Neuropeptide AF receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
IUPHAR BPS Guide to Pharmacology CITE, 2019Co-Authors: Catherine Mollereau-manaute, Kazuyoshi Tsutsui, Michel Roumy, Lionel Moulédous, Takayoshi Ubuka, Jeanmarie ZajacAbstract:The Neuropeptide FF receptor family contains two subtypes, NPFF1 and NPFF2 (provisional nomenclature [10]), which exhibit high aFFinities for Neuropeptide FF (NPFF, O15130) and RFamide related peptides (RFRP: precursor gene symbol NPVF, Q9HCQ7). NPFF1 is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus. NPFF2 is present in high density in the superficial layers of the mammalian spinal cord where it is involved in nociception and modulation of opioid functions.
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Modulation de conductances calciques par les peptides opioïdes et anti-opioïdes
'EDP Sciences', 2017Co-Authors: Michel Roumy, Jeanmarie ZajacAbstract:Dans le système nerveux central, l’activation des canaux Ca2+ dépendant du potentiel déclenche la libération des neurotransmetteurs chimiques. L’activité de ces canaux est modulée par un grand nombre de récepteurs membranaires, en particulier ceux couplés aux protéines G. Dans cette revue, nous décrivons la modulation des canaux Ca2+ par les peptides opioïdes et antiopioïdes. Après une brève présentation des systèmes opioïdes, nous décrivons les caractéristiques de l’inhibition des canaux Ca2+ par l’activation de ces systèmes. Le Neuropeptide FF à été pris comme exemple de système anti-opioïde. Après avoir résumé les avancées récentes dans la connaissance de ce système, nous exposons les résultats, obtenus dans notre laboratoire, qui démontrent une activité anti-opioïde du NPFF, dans la modulation des canaux Ca2+ de neurones isolés
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Abbreviations: 1DMe, [-Tyr 1,(NMe)Phe
2016Co-Authors: Lionel Moulédous, Soren Merker, Jérémie Neasta, Benoit Roux, Jeanmarie ZajacAbstract:Neuropeptide FF-sensitive confinement of mu opioi
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currents in a dorsal root ganglion cell line
2013Co-Authors: Short Communication, Catherine Mollereau, Michel Roumy, Jeanmarie ZajacAbstract:This study investigated the presence of Neuropeptide FF (NPFF) receptors on F-11 cells, a hybridoma derived from rat dorsal root ganglia (DRG) and mouse neuroblastoma. Binding experiments revealed a low density (4 fmol/mg) of high aFFinity (0.5 nM) [ 3 H]-EYF binding sites in these cells. The whole-cell planar patch-clamp technique showed that dNPA, a selective NPFF2 agonist, increased the voltage-dependent potassium outward currents (about 30 pA/pF) by 21%; this reversible eFFect on sustained delayed potassium currents is blocked by tetraethylammonium. The similar eFFects of NPFF and opioid agonists on K + currents in this cell line may explain their similar antinociceptive actions at the spinal level. Key words: Neuropeptide FF, receptor, neuroblastoma F-11 cell, K + current, opioi
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opioid modulating peptides mechanisms of action
Current Topics in Medicinal Chemistry, 2005Co-Authors: Catherine Mollereau, Michel Roumy, Jeanmarie ZajacAbstract:Opioids are involved in the physiological control of numerous functions of the central nervous system, particularly nociception. It appears that some endogenous Neuropeptides, called “anti-opioids“, participate in an homeostatic system tending to reduce the eFFects of opioids. Neuropeptide FF (NPFF) and cholecystokinin (CCK) possess these properties and, paradoxically, the opioid peptides nociceptin and dynorphin display some anti-opioid activity. All these peptides exhibit complex properties as they are able to both counteract and potentiate opioid activity, acting rather as modulators of opioid functions. The purpose of this review is to highlight that two diFFerent mechanisms are clearly involved in the control of opioid functions by opioid-modulating peptides: a “circuitry-induced” mechanism for nociceptin and dynorphin, and a “cellular anti-opioid” mechanism for NPFF and CCK. The knowledge of these mechanisms has potential therapeutic interest in the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.
Guy Simonnet - One of the best experts on this subject based on the ideXlab platform.
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Aminoguanidine Hydrazone Derivatives as Nonpeptide NPFF1 Receptor Antagonists Reverse Opioid Induced Hyperalgesia
2018Co-Authors: Hassan Hammoud, Khadija Elhabazi, Raphäelle Quillet, Isabelle Bertin, Valérie Utard, Emilie Laboureyras, Jean-jacques Bourguignon, Frédéric Bihel, Guy Simonnet, Frédéric SimoninAbstract:Neuropeptide FF receptors (NPFF1R and NPFF2R) and their endogenous ligand Neuropeptide FF have been shown previously to display antiopioid properties and to play a critical role in the adverse eFFects associated with chronic administrations of opiates including the development of opioid-induced hyperalgesia and analgesic tolerance. In this work, we sought to identify novel NPFF receptors ligands by focusing our interest in a series of heterocycles as rigidified nonpeptide NPFF receptor ligands, starting from already described aminoguanidine hydrazones (AGHs). Binding experiments and functional assays highlighted AGH 1n and its rigidified analogue 2-amino-dihydropyrimidine 22e for in vivo experiments. As shown earlier with the prototypical dipeptide antagonist RF9, both 1n and 22e reduced significantly the long lasting fentanyl-induced hyperalgesia in rodents. Altogether these data indicate that AGH rigidification maintains nanomolar aFFinities for both NPFF receptors, while improving antagonist character toward NPFF1R
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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
Neuropsychopharmacology, 2017Co-Authors: Khadija Elhabazi, Martine Schmitt, Raphäelle Quillet, Isabelle Bertin, Valérie Utard, Emilie Laboureyras, Jean-jacques Bourguignon, Jean-paul Humbert, Meric Ben Boujema, Guy SimonnetAbstract: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.
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characterization of binding sites for Neuropeptide FF on t lymphocytes of the jurkat cell line
Peptides, 1995Co-Authors: M Minault, Guy Simonnet, J C Lecron, S Labrouche, J GombertAbstract:Abstract Neuropeptide FF (NPFF) is a Neuropeptide with antiopiate properties able to antagonize the action of both endogenous and exogenous opiates. Because we have recently shown that NPFF modulates the proliferation of human T lymphocytes, we have searched for binding sites for this peptide on T lymphocytes. Our study shows that T lymphocytes of the Jurkat cell line express binding sites for [ 125 I]YLFQPQRFamide, an iodinated analogue of NPFF. This binding is time and dose dependent, reversible, saturable, and may be resolved in two distinct components of high and low aFFinity. The opiate receptor agonists μ, δ, and κ, as well the antagonist naloxone, were unable to aFFect binding. Beside the eFFects of opiates on immune cells, our results suggest that an antiopiate peptide, such as NPFF, could play a role in the modulation of the immune system.
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NPFF, a FMRF-NH2-like peptide, blocks opiate eFFects on ileum contractions.
Peptides, 1993Co-Authors: Patricia Demichel, Juan Carlos Rodriguez, Jacques Roquebert, Guy SimonnetAbstract:We studied the ability of NPFF, a FMRFamide-like peptide with certain antiopiate properties, to aFFect the inhibitory eFFect of morphine on the electrically induced contraction of guinea pig ileum. Neuropeptide FF had no eFFect when administered alone but reduced morphine inhibition in a noncompetitive manner. Neuropeptide FF also altered the inhibitory eFFect of opioid peptides as released by an intense electrical stimulation at 10 Hz. These results suggest that NPFF receptors exist in guinea pig ileum in association with opiate receptors, and that endogenous NPFF may play a role in the diarrhea observed in the morphine withdrawal syndrome.
Martine Schmitt - One of the best experts on this subject based on the ideXlab platform.
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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
Neuropsychopharmacology, 2017Co-Authors: Khadija Elhabazi, Martine Schmitt, Raphäelle Quillet, Isabelle Bertin, Valérie Utard, Emilie Laboureyras, Jean-jacques Bourguignon, Jean-paul Humbert, Meric Ben Boujema, Guy SimonnetAbstract: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.
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The eFFect of Neuropeptide FF in the amygdala kindling model.
Acta neurologica Scandinavica, 2015Co-Authors: Ine Buffel, Robrecht Raedt, Veerle De Herdt, Alfred Meurs, Wytse J. Wadman, Jeanelle Portelli, Lindsay Poppe, V. De Meulenaere, Frédéric Bihel, Martine SchmittAbstract:Objective Neuropeptide FF (NPFF) and its receptors (NPFF1R and NPFF2R) are diFFerentially distributed throughout the central nervous system. NPFF reduces cortical excitability in rats when administered intracerebroventricularly (i.c.v.), and both NPFF and NPFF1R antagonists attenuate pilocarpine-induced limbic seizures. In this study, our aim was to determine whether NPFF exerts anticonvulsant or anti-epileptogenic eFFects in the rat amygdala kindling model for temporal lobe seizures. Methods Male Wistar rats were implanted with a recording/stimulation electrode in the right amygdala and a cannula in the left lateral ventricle. In a first group of animals, the afterdischarge threshold (ADT) was determined after a single i.c.v. infusion of saline (n = 8) or NPFF (1 nmol/h for 2 h; n = 10). Subsequently, daily infusion of saline (n = 8) or NPFF (1 nmol/h for 2 h; i.c.v.; n = 9) was performed, followed by a kindling stimulus (ADT+200 μA). Afterdischarge duration and seizure severity were evaluated after every kindling stimulus. A second group of rats (n = 7) were fully kindled, and the eFFect of saline or a high dose of NPFF (10 nmol/h for 2 h, i.c.v.) on ADT and the generalized seizure threshold (GST) was subsequently determined. Results In naive rats, NPFF significantly increased the ADT compared to control (435 ± 72 μA vs 131 ± 23 μA [P < 0.05]). When rats underwent daily stimulations above the ADT, NPFF did not delay or prevent kindling acquisition. Furthermore, a high dose of NPFF did not alter ADT or GST in fully kindled rats. Conclusions I.c.v. administration of NPFF reduced excitability in the amygdala in naive, but not in fully kindled rats, and had no eFFect on kindling acquisition.
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Neuropeptide FF and prolactin releasing peptide decrease cortical excitability through activation of npFF receptors
Epilepsia, 2015Co-Authors: Ine Buffel, Robrecht Raedt, Veerle De Herdt, Alfred Meurs, Wytse J. Wadman, Jeanelle Portelli, Frédéric Bihel, Martine Schmitt, Lynn Sioncke, Kristl VonckAbstract:Summary Objective Drugs with a novel mechanism of action are needed to reduce the number of people with epilepsy that are refractory to treatment. Increasing attention is paid to Neuropeptide systems and several anticonvulsant Neuropeptides have already been described, such as galanin, ghrelin, and Neuropeptide Y (NPY). Many others, however, have not been investigated for their ability to aFFect epileptic seizures. In this study, the potential anticonvulsant activities of three members of the RF-amide Neuropeptide family, Neuropeptide FF (NPFF), prolactin-releasing peptide (PrRP), and kisspeptin (Kp) and other receptor ligands (NPFF1/2R, GPR10, and GRP54, respectively) were tested in the motor cortex stimulation model. Methods A train of pulses with increasing intensity (0–10 mA over 150 s, 50 Hz, pulse width 2 msec) was delivered to the motor cortex of rats. The threshold intensity for eliciting a motor response (i.e., motor threshold) was determined through behavioral observation and used as a measure for cortical excitability. The threshold was determined before, during, and after the intracerebroventricular (i.c.v.) administration of various NPFF1/2R, GPR10, and GPR54 receptor ligands. Results NPFF and PrRP significantly increased the motor threshold by a maximum of 143 ± 27 and 83 ± 13 μA, respectively, for the doses of 1 nmol/h (p < 0.05). The increase of motor threshold by NPFF and PrRP was prevented by pretreatment and co-treatment with the NPFF1/2R antagonist RF9. Pretreatment with a selective NPFF1R antagonist also prevented the threshold increase induced by NPFF. Kp did not increase motor threshold. Significance Intracerebroventricular infusion of NPFF or PrRP decreases cortical excitability in rats through activation of NPFFRs. Furthermore, the NPFF1R is required for the NPFF-induced decrease in cortical excitability.
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Development of a Peptidomimetic Antagonist of Neuropeptide FF Receptors for the Prevention of Opioid-Induced Hyperalgesia
2015Co-Authors: Frédéric Bihel, Martine Schmitt, Isabelle Bertin, Emilie Laboureyras, Jean-paul Humbert, Séverine Schneider, Patrick Wagner, Benoît Petit-demoulière, Elodie Schneider, Catherine MollereauAbstract:Through the development of a new class of unnatural ornithine derivatives as bioisosteres of arginine, we have designed an orally active peptidomimetic antagonist of Neuropeptide FF receptors (NPFFR). Systemic low-dose administration of this compound to rats blocked opioid-induced hyperalgesia, without any apparent side-eFFects. Interestingly, we also observed that this compound potentiated opioid-induced analgesia. This unnatural ornithine derivative provides a novel therapeutic approach for both improving analgesia and reducing hyperalgesia induced by opioids in patients being treated for chronic pain
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rf9 a potent and selective Neuropeptide FF receptor antagonist prevents opioid induced tolerance associated with hyperalgesia
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Frederic Simonin, Martine Schmitt, Patrick Laurent, Catherine Mollereau, Emilie Laboureyras, Jeanpaul Laulin, Audrey Matifas, Jack H. Jhamandas, David Mactavish, Marc ParmentierAbstract:Neuropeptide FF (NPFF) has been proposed to play a role in pain modulation, opioid tolerance, and several other physiological processes. However, pharmacological agents that would help define physiological roles for this peptide are still missing. Here we report the discovery of a potent and selective NPFF receptor antagonist, RF9, that can be administered systemically. This compound does not show any eFFects by itself but can block eFFiciently the increase in blood pressure and heart rate evoked by NPFF. When chronically coinjected with heroin, RF9 completely blocks the delayed and long-lasting paradoxical opioid-induced hyperalgesia and prevents the development of associated tolerance. Our data indicate that NPFF receptors are part of a bona fide antiopioid system and that selective antagonists of these receptors could represent useful therapeutic agents for improving the eFFicacy of opioids in chronic pain treatment.
Marc Parmentier - One of the best experts on this subject based on the ideXlab platform.
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rf9 a potent and selective Neuropeptide FF receptor antagonist prevents opioid induced tolerance associated with hyperalgesia
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Frederic Simonin, Martine Schmitt, Patrick Laurent, Catherine Mollereau, Emilie Laboureyras, Jeanpaul Laulin, Audrey Matifas, Jack H. Jhamandas, David Mactavish, Marc ParmentierAbstract:Neuropeptide FF (NPFF) has been proposed to play a role in pain modulation, opioid tolerance, and several other physiological processes. However, pharmacological agents that would help define physiological roles for this peptide are still missing. Here we report the discovery of a potent and selective NPFF receptor antagonist, RF9, that can be administered systemically. This compound does not show any eFFects by itself but can block eFFiciently the increase in blood pressure and heart rate evoked by NPFF. When chronically coinjected with heroin, RF9 completely blocks the delayed and long-lasting paradoxical opioid-induced hyperalgesia and prevents the development of associated tolerance. Our data indicate that NPFF receptors are part of a bona fide antiopioid system and that selective antagonists of these receptors could represent useful therapeutic agents for improving the eFFicacy of opioids in chronic pain treatment.
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The prolactin-releasing peptide antagonizes the opioid system through its receptor GPR10
Nature Neuroscience, 2005Co-Authors: Patrick Laurent, Jérôme Becker, Olga Valverde, Catherine Ledent, Alban De Kerchove D'exaerde, Serge N. Schiffmann, Rafael Maldonado, Gilbert Vassart, Marc ParmentierAbstract:Prolactin-releasing peptide (PrRP) and its receptor G protein-coupled receptor 10 (GPR10) are expressed in brain areas involved in the processing of nociceptive signals. We investigated the role of this new Neuropeptidergic system in GPR10-knockout mice. These mice had higher nociceptive thresholds and stronger stress-induced analgesia than wild-type mice, diFFerences that were suppressed by naloxone treatment. In addition, potentiation of morphine-induced antinociception and reduction of morphine tolerance were observed in mutants. Intracerebroventricular administration of PrRP in wild-type mice promoted hyperalgesia and reversed morphine-induced antinociception. PrRP administration had no eFFect on GPR10-mutant mice, showing that its eFFects are mediated by GPR10. Anti-opioid eFFects of Neuropeptide FF were found to require a functional PrRP-GPR10 system. Finally, GPR10 deficiency enhanced the acquisition of morphine-induced conditioned place preference and decreased the severity of naloxone-precipitated morphine withdrawal syndrome. Altogether, our data identify the PrRP-GPR10 system as a new and potent negative modulator of the opioid system.
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functional characterization of a human receptor for Neuropeptide FF and related peptides
British Journal of Pharmacology, 2001Co-Authors: Masato Kotani, Gilbert Vassart, Catherine Mollereau, Jeanmarie Zajac, Michel Detheux, Emmanuel Le Poul, Stephane Brezillon, Jalal Vakili, Honore Mazarguil, Marc ParmentierAbstract:1. Neuropeptides FF (NPFF) and AF (NPAF) are involved in pain modulation and opioid tolerance. These peptides were known to act through uncharacterized G protein-coupled receptors (GPCR). We describe here, using an aequorin-based assay as screening tool, that an orphan GPCR, previously designated HLWAR77, is a functional high aFFinity receptor for NPFF and related peptides. This receptor is further designated as NPFFR. 2. Binding experiments were performed with a new radioiodinated probe, [(125)I]-EYF, derived from the EFW-NPSF sequence of the rat NPFF precursor. Chinese hamster ovary (CHO) cell membranes expressing NPFFR bound [(125)I]-EYF with a K(d) of 0.06 nM. Various NPFF analogues and related peptides inhibited [(125)I]-EYF specific binding with the following rank order (K(i)): human NPAF (0.22 nM), SQA-NPFF (0.29 nM), NPFF (0.30 nM), 1DMe (0.31 nM), EYW-NPSF (0.32 nM), QFW-NPSF (0.35 nM), 3D (1.12 nM), Met-enk-RF-NH(2) (3.25 nM), FMRF-NH(2) (10.5 nM) and NPSF (12.1 nM). 3. The stimulatory activity of the same set of peptides was measured by a functional assay based on the co-expression of NPFFR, G(alpha 16) and apoaequorin. The rank order of potency was consistent with the results of the binding assay. 4. Membranes from NPFFR expressing CHO cells bound GTP gamma[(35)S] in the presence of SQA-NPFF. This functional response was prevented by pertussis toxin treatment, demonstrating the involvement of G(i) family members. 5. SQA-NPFF inhibited forskolin induced cyclic AMP accumulation in recombinant CHO cells in a dose dependent manner. This response was abolished as well by pertussis toxin pre-treatment. 6. RT -- PCR analysis of human tissues mRNA revealed that expression of NPFFR was mainly detected in placenta, thymus and at lower levels in pituitary gland, spleen and testis.