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Zilong Wang - One of the best experts on this subject based on the ideXlab platform.
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pharmacological characterization of en 9 a novel chimeric peptide of endomorphin 2 and neuropeptide ff that produces potent antinociceptive activity and limited tolerance
Neuropharmacology, 2016Co-Authors: Zilong Wang, Quan Fang, Zhenglan Han, Honghai Tang, Pei Wang, Jing-jing Song, Ting Zhang, Run Zhang, Meng-na Zhang, Rui WangAbstract:Mounting evidences indicate the functional interactions between neuropeptide FF (NPFF) and opioids, including the endogenous opioids. In the present work, EN-9, a chimeric peptide containing the functional domains of the endogenous opioid endomorphin-2 (EM-2) and NPFF, was synthesized and pharmacologically characterized. In vitro cAMP assay demonstrated that EN-9 was a multifunctional agonist of κ-opioid, NPFF1 and NPFF2 receptors. In the mouse tail-flick test, intracerebroventricularly (i.c.v.) administration of EN-9 produced significant antinociception with an ED50 value of 13.44 nmol, which lasted longer than that of EM-2. In addition, EN-9 induced potent antinociception after both intravenous (i.v.) and subcutaneous (s.c.) injection. Furthermore, the experiments using the antagonists of opioid and NPFF receptors indicated that the central antinociception of EN-9 was mainly mediated by κ-opioid receptor, independently on NPFF receptors. Notably, the central antinociception of EN-9 was not reduced over a period of 6 days repeated i.c.v. injection. Repeated i.c.v. administration of EN-9 with the NPFF1 and NPFF2 receptors antagonist RF9 resulted in a progressive loss of analgesic potency, consistent with the development of tolerance. Moreover, central administration of EN-9 induced the place conditioning aversion only at a high dose of 60 nmol, but not at low doses. At supraspinal level, only high dose of EN-9 (60 nmol, i.c.v.) inhibited gastrointestinal transit via NPFF receptors. Similarly, systemic administration of EN-9 also inhibited gastrointestinal transit at high doses (10 and 30 mg/kg, i.v.). Taken together, the multifunctional agonist of κ-opioid and NPFF receptors EN-9 produced a potent, non-tolerance forming antinociception with limited side effects.
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bn 9 a chimeric peptide with mixed opioid and neuropeptide ff receptor agonistic properties produces nontolerance forming antinociception in mice
British Journal of Pharmacology, 2016Co-Authors: Zhenglan Han, Zilong Wang, Quan Fang, Yulong Sun, Jing-jing Song, Ting Zhang, Run Zhang, Meng-na Zhang, Yanhong Xing, Rui WangAbstract:BACKGROUND AND PURPOSE Neuropeptide FF (NPFF) behaves as an endogenous opioid-modulating peptide. In the present study, the opioid and NPFF pharmacophore-containing chimeric peptide BN-9 was synthesized and pharmacologically characterized. EXPERIMENTAL APPROACH Agonist activities of BN-9 at opioid and NPFF receptors were characterized in in vitro cAMP assays. Antinociceptive activities of BN-9 were evaluated in the mouse tail-flick and formalin tests. Furthermore, its side effects were investigated in rotarod, antinociceptive tolerance, reward and gastrointestinal transit tests. KEY RESULTS BN-9 acted as a novel multifunctional agonist at mu, delta, kappa, NPFF1 and NPFF2 receptors in cAMP assays. In the tail-flick test, BN-9 produced dose-related antinociception and was approximately equipotent to morphine; this antinociception was blocked by mu and kappa receptor antagonists, but not by the d receptor antagonist. In the formalin test, supraspinal administration of BN-9 produced significant analgesia. Notably, repeated administration of BN-9 produced analgesia without loss of potency over 8 days. In contrast, repeated i.c.v. co-administration of BN-9 with the NPFF receptor antagonist RF9 produced significant antinociceptive tolerance. Furthermore, i.c.v. BN-9 induced conditioned place preference. When given by the same routes, BN-9 had a more than eightfold higher ED50 value for gastrointestinal transit inhibition compared with the ED50 values for antinociception. CONCLUSIONS AND IMPLICATIONS BN-9 produced a robust, nontolerance-forming analgesia with limited inhibition of gastrointestinal transit. As BN-9 is able to activate both opioid and NPFF systems, this provides an interesting approach for the development of novel analgesics with minimal side effects.
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Structure-Based Optimization of Multifunctional Agonists for Opioid and Neuropeptide FF Receptors with Potent Nontolerance Forming Analgesic Activities
2016Co-Authors: Zilong Wang, Jiaxin Pan, Honghai Tang, Jing-jing Song, Ting Zhang, Run Zhang, Meng-na ZhangAbstract:The opioid and neuropeptide FF pharmacophore-containing chimeric peptide 0 (BN-9) was recently developed and produced potent nontolerance forming analgesia. In this study, 11 analogues of 0 were designed and synthesized. An in vitro cAMP assay demonstrated that these analogues behaved as multifunctional agonists at both opioid and NPFF receptors. In mouse tail-flick test, most of the analogues produced potent nontolerance forming antinociception. Notably, 11 (DN-9) was 33-fold more potent than 0 at analgesic effects, which was mediated by μ- and κ-opioid receptors. In addition, 11 also produced powerful analgesic effects in the formalin pain and CFA-induced chronic inflammatory pain models. Strikingly, following its repeated administration for 6 days, 11 did not produce antinociceptive tolerance in the tail-flick test and CFA-induced pain model. The present work indicates that it is reasonable to design multifunctional peptide ligands for opioid and NPFF receptors in a single molecule producing effective nontolerance forming antinociception
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opposite effects of neuropeptide ff on central antinociception induced by endomorphin 1 and endomorphin 2 in mice
PLOS ONE, 2014Co-Authors: Zilong Wang, Quan Fang, Zhenglan Han, Jiaxin Pan, Honghai Tang, Pei Wang, Ting Zheng, Xuemei Chang, Rui WangAbstract:Neuropeptide FF (NPFF) is known to be an endogenous opioid-modulating peptide. Nevertheless, very few researches focused on the interaction between NPFF and endogenous opioid peptides. In the present study, we have investigated the effects of NPFF system on the supraspinal antinociceptive effects induced by the endogenous µ-opioid receptor agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2). In the mouse tail-flick assay, intracerebroventricular injection of EM-1 induced antinociception via µ-opioid receptor while the antinociception of intracerebroventricular injected EM-2 was mediated by both µ- and κ-opioid receptors. In addition, central administration of NPFF significantly reduced EM-1-induced central antinociception, but enhanced EM-2-induced central antinociception. The results using the selective NPFF1 and NPFF2 receptor agonists indicated that the EM-1-modulating action of NPFF was mainly mediated by NPFF2 receptor, while NPFF potentiated EM-2-induecd antinociception via both NPFF1 and NPFF2 receptors. To further investigate the roles of µ- and κ-opioid systems in the opposite effects of NPFF on central antinociception of endomprphins, the µ- and κ-opioid receptors selective agonists DAMGO and U69593, respectively, were used. Our results showed that NPFF could reduce the central antinociception of DAMGO via NPFF2 receptor and enhance the central antinociception of U69593 via both NPFF1 and NPFF2 receptors. Taken together, our data demonstrate that NPFF exerts opposite effects on central antinociception of endomorphins and provide the first evidence that NPFF potentiate antinociception of EM-2, which might result from the interaction between NPFF and κ-opioid systems.
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Dose-related effects of i.c.v. administration of NPFF on the central antinociception of EM-1 (i.c.v.) (A) and EM-2 (i.c.v.) (B), in mouse tail-flick assays.
2014Co-Authors: Zilong Wang, Quan Fang, Zhenglan Han, Jiaxin Pan, Honghai Tang, Pei Wang, Ting Zheng, Xuemei ChangAbstract:(A) NPFF (3, 10 and 15 nmol) reduced 7.5 nmol EM-1-induced central antinociception. (B) NPFF (3, 10 and 15 nmol) potentiated 7.5 nmol EM-2-induced central antinociception. Each value represents mean ± S.E.M. (n = 7–12 mice/group). ***p
Rui Wang - One of the best experts on this subject based on the ideXlab platform.
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pharmacological characterization of en 9 a novel chimeric peptide of endomorphin 2 and neuropeptide ff that produces potent antinociceptive activity and limited tolerance
Neuropharmacology, 2016Co-Authors: Zilong Wang, Quan Fang, Zhenglan Han, Honghai Tang, Pei Wang, Jing-jing Song, Ting Zhang, Run Zhang, Meng-na Zhang, Rui WangAbstract:Mounting evidences indicate the functional interactions between neuropeptide FF (NPFF) and opioids, including the endogenous opioids. In the present work, EN-9, a chimeric peptide containing the functional domains of the endogenous opioid endomorphin-2 (EM-2) and NPFF, was synthesized and pharmacologically characterized. In vitro cAMP assay demonstrated that EN-9 was a multifunctional agonist of κ-opioid, NPFF1 and NPFF2 receptors. In the mouse tail-flick test, intracerebroventricularly (i.c.v.) administration of EN-9 produced significant antinociception with an ED50 value of 13.44 nmol, which lasted longer than that of EM-2. In addition, EN-9 induced potent antinociception after both intravenous (i.v.) and subcutaneous (s.c.) injection. Furthermore, the experiments using the antagonists of opioid and NPFF receptors indicated that the central antinociception of EN-9 was mainly mediated by κ-opioid receptor, independently on NPFF receptors. Notably, the central antinociception of EN-9 was not reduced over a period of 6 days repeated i.c.v. injection. Repeated i.c.v. administration of EN-9 with the NPFF1 and NPFF2 receptors antagonist RF9 resulted in a progressive loss of analgesic potency, consistent with the development of tolerance. Moreover, central administration of EN-9 induced the place conditioning aversion only at a high dose of 60 nmol, but not at low doses. At supraspinal level, only high dose of EN-9 (60 nmol, i.c.v.) inhibited gastrointestinal transit via NPFF receptors. Similarly, systemic administration of EN-9 also inhibited gastrointestinal transit at high doses (10 and 30 mg/kg, i.v.). Taken together, the multifunctional agonist of κ-opioid and NPFF receptors EN-9 produced a potent, non-tolerance forming antinociception with limited side effects.
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bn 9 a chimeric peptide with mixed opioid and neuropeptide ff receptor agonistic properties produces nontolerance forming antinociception in mice
British Journal of Pharmacology, 2016Co-Authors: Zhenglan Han, Zilong Wang, Quan Fang, Yulong Sun, Jing-jing Song, Ting Zhang, Run Zhang, Meng-na Zhang, Yanhong Xing, Rui WangAbstract:BACKGROUND AND PURPOSE Neuropeptide FF (NPFF) behaves as an endogenous opioid-modulating peptide. In the present study, the opioid and NPFF pharmacophore-containing chimeric peptide BN-9 was synthesized and pharmacologically characterized. EXPERIMENTAL APPROACH Agonist activities of BN-9 at opioid and NPFF receptors were characterized in in vitro cAMP assays. Antinociceptive activities of BN-9 were evaluated in the mouse tail-flick and formalin tests. Furthermore, its side effects were investigated in rotarod, antinociceptive tolerance, reward and gastrointestinal transit tests. KEY RESULTS BN-9 acted as a novel multifunctional agonist at mu, delta, kappa, NPFF1 and NPFF2 receptors in cAMP assays. In the tail-flick test, BN-9 produced dose-related antinociception and was approximately equipotent to morphine; this antinociception was blocked by mu and kappa receptor antagonists, but not by the d receptor antagonist. In the formalin test, supraspinal administration of BN-9 produced significant analgesia. Notably, repeated administration of BN-9 produced analgesia without loss of potency over 8 days. In contrast, repeated i.c.v. co-administration of BN-9 with the NPFF receptor antagonist RF9 produced significant antinociceptive tolerance. Furthermore, i.c.v. BN-9 induced conditioned place preference. When given by the same routes, BN-9 had a more than eightfold higher ED50 value for gastrointestinal transit inhibition compared with the ED50 values for antinociception. CONCLUSIONS AND IMPLICATIONS BN-9 produced a robust, nontolerance-forming analgesia with limited inhibition of gastrointestinal transit. As BN-9 is able to activate both opioid and NPFF systems, this provides an interesting approach for the development of novel analgesics with minimal side effects.
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opposite effects of neuropeptide ff on central antinociception induced by endomorphin 1 and endomorphin 2 in mice
PLOS ONE, 2014Co-Authors: Zilong Wang, Quan Fang, Zhenglan Han, Jiaxin Pan, Honghai Tang, Pei Wang, Ting Zheng, Xuemei Chang, Rui WangAbstract:Neuropeptide FF (NPFF) is known to be an endogenous opioid-modulating peptide. Nevertheless, very few researches focused on the interaction between NPFF and endogenous opioid peptides. In the present study, we have investigated the effects of NPFF system on the supraspinal antinociceptive effects induced by the endogenous µ-opioid receptor agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2). In the mouse tail-flick assay, intracerebroventricular injection of EM-1 induced antinociception via µ-opioid receptor while the antinociception of intracerebroventricular injected EM-2 was mediated by both µ- and κ-opioid receptors. In addition, central administration of NPFF significantly reduced EM-1-induced central antinociception, but enhanced EM-2-induced central antinociception. The results using the selective NPFF1 and NPFF2 receptor agonists indicated that the EM-1-modulating action of NPFF was mainly mediated by NPFF2 receptor, while NPFF potentiated EM-2-induecd antinociception via both NPFF1 and NPFF2 receptors. To further investigate the roles of µ- and κ-opioid systems in the opposite effects of NPFF on central antinociception of endomprphins, the µ- and κ-opioid receptors selective agonists DAMGO and U69593, respectively, were used. Our results showed that NPFF could reduce the central antinociception of DAMGO via NPFF2 receptor and enhance the central antinociception of U69593 via both NPFF1 and NPFF2 receptors. Taken together, our data demonstrate that NPFF exerts opposite effects on central antinociception of endomorphins and provide the first evidence that NPFF potentiate antinociception of EM-2, which might result from the interaction between NPFF and κ-opioid systems.
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Opposite Effects of Neuropeptide FF on Central Antinociception Induced by Endomorphin-1 and Endomorphin-2 in Mice
2014Co-Authors: Ting Zheng, Xuemei Chang, Rui WangAbstract:Neuropeptide FF (NPFF) is known to be an endogenous opioid-modulating peptide. Nevertheless, very few researches focused on the interaction between NPFF and endogenous opioid peptides. In the present study, we have investigated the effects of NPFF system on the supraspinal antinociceptive effects induced by the endogenous m-opioid receptor agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2). In the mouse tail-flick assay, intracerebroventricular injection of EM-1 induced antinociception via m-opioid receptor while the antinociception of intracerebroventricular injected EM-2 was mediated by both m- and k-opioid receptors. In addition, central administration of NPFF significantly reduced EM-1-induced central antinociception, but enhanced EM-2-induced central antinociception. The results using the selective NPFF1 and NPFF2 receptor agonists indicated that the EM-1-modulating action of NPFF was mainly mediated by NPFF2 receptor, while NPFF potentiated EM-2-induecd antinociception via both NPFF1 and NPFF2 receptors. To further investigate the roles of m-and k-opioid systems in the opposite effects of NPFF on central antinociception of endomprphins, the m- and k-opioid receptors selective agonists DAMGO and U69593, respectively, were used. Our results showed that NPFF could reduce the central antinociception of DAMGO via NPFF2 receptor and enhance the central antinociception of U69593 via both NPFF1 and NPFF2 receptors. Taken together, our data demonstrate that NPFF exerts opposite effects on central antinociception of endomorphins and provide the first evidence that NPFF potentiate antinociception of EM-2, which might result from th
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neuropeptide ff attenuates the acquisition and the expression of conditioned place aversion to endomorphin 2 in mice
Behavioural Brain Research, 2013Co-Authors: Zhenglan Han, Zilong Wang, Quan Fang, Hongzhu Tang, Xiongli Yang, Xiaoyu Zhang, Rui WangAbstract:It has been demonstrated that the endogenous mu opioid (MOP) agonist endomorphin-2 (EM-2) produces conditioned place aversion (CPA) and in contrast, morphine exerts opposite action. Neuropeptide FF (NPFF) was reported to act as a functional antagonist of mu opioid receptor and to exert opioid-modulating activities. The present study examined the influence of NPFF on the rewarding action of EM-2, using the unbiased conditioned place preference (CPP) paradigm. For testing the effect of NPFF on the acquisition of EM-2-induced CPA, NPFF and EM-2 were co-injected on the conditioning days without drug treatment on the followed test day. To explore the effect of NPFF on the expression of EM-2-induced CPA, EM-2 was administered alone on the conditioning days, and NPFF was given 5 min before placement in the CPP apparatus on the test day. The results showed that NPFF (2.5, 5 and 10 nmol, i.c.v.) alone caused little place preference change. However, NPFF dose-dependently reversed the acquisition of CPA induced by 30 nmol EM-2 (i.c.v.). Similarly, the expression of EM-2-induced CPA was also reduced by NPFF. Moreover, the effects of NPFF on the acquisition and the expression of EM-2-induced CPA were completely blocked by the NPFF receptors antagonist RF9 (10 nmol, i.c.v.). However, central injection of NPFF neither changed the locomotor activity nor modified the locomotor action of EM-2. These data provide the first evidence for a functional interaction of the endogenous ligands for NPFF and MOP receptors, and further support an anti-opioid character of NPFF system.
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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Endogenous mammalian RF-amide peptides, including PrRP, kisspeptin and 26RFa, modulate nociception and morphine analgesia via NPFF receptors
Neuropharmacology, 2013Co-Authors: Khadija Elhabazi, Frédéric Bihel, Martine Schmitt, Isabelle Bertin, Jean-jacques Bourguignon, Jean-paul Humbert, Bernard Bucher, Jérôme Becker, Tania Sorg, Hamid MezianeAbstract: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.
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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.
Quan Fang - One of the best experts on this subject based on the ideXlab platform.
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pharmacological characterization of en 9 a novel chimeric peptide of endomorphin 2 and neuropeptide ff that produces potent antinociceptive activity and limited tolerance
Neuropharmacology, 2016Co-Authors: Zilong Wang, Quan Fang, Zhenglan Han, Honghai Tang, Pei Wang, Jing-jing Song, Ting Zhang, Run Zhang, Meng-na Zhang, Rui WangAbstract:Mounting evidences indicate the functional interactions between neuropeptide FF (NPFF) and opioids, including the endogenous opioids. In the present work, EN-9, a chimeric peptide containing the functional domains of the endogenous opioid endomorphin-2 (EM-2) and NPFF, was synthesized and pharmacologically characterized. In vitro cAMP assay demonstrated that EN-9 was a multifunctional agonist of κ-opioid, NPFF1 and NPFF2 receptors. In the mouse tail-flick test, intracerebroventricularly (i.c.v.) administration of EN-9 produced significant antinociception with an ED50 value of 13.44 nmol, which lasted longer than that of EM-2. In addition, EN-9 induced potent antinociception after both intravenous (i.v.) and subcutaneous (s.c.) injection. Furthermore, the experiments using the antagonists of opioid and NPFF receptors indicated that the central antinociception of EN-9 was mainly mediated by κ-opioid receptor, independently on NPFF receptors. Notably, the central antinociception of EN-9 was not reduced over a period of 6 days repeated i.c.v. injection. Repeated i.c.v. administration of EN-9 with the NPFF1 and NPFF2 receptors antagonist RF9 resulted in a progressive loss of analgesic potency, consistent with the development of tolerance. Moreover, central administration of EN-9 induced the place conditioning aversion only at a high dose of 60 nmol, but not at low doses. At supraspinal level, only high dose of EN-9 (60 nmol, i.c.v.) inhibited gastrointestinal transit via NPFF receptors. Similarly, systemic administration of EN-9 also inhibited gastrointestinal transit at high doses (10 and 30 mg/kg, i.v.). Taken together, the multifunctional agonist of κ-opioid and NPFF receptors EN-9 produced a potent, non-tolerance forming antinociception with limited side effects.
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bn 9 a chimeric peptide with mixed opioid and neuropeptide ff receptor agonistic properties produces nontolerance forming antinociception in mice
British Journal of Pharmacology, 2016Co-Authors: Zhenglan Han, Zilong Wang, Quan Fang, Yulong Sun, Jing-jing Song, Ting Zhang, Run Zhang, Meng-na Zhang, Yanhong Xing, Rui WangAbstract:BACKGROUND AND PURPOSE Neuropeptide FF (NPFF) behaves as an endogenous opioid-modulating peptide. In the present study, the opioid and NPFF pharmacophore-containing chimeric peptide BN-9 was synthesized and pharmacologically characterized. EXPERIMENTAL APPROACH Agonist activities of BN-9 at opioid and NPFF receptors were characterized in in vitro cAMP assays. Antinociceptive activities of BN-9 were evaluated in the mouse tail-flick and formalin tests. Furthermore, its side effects were investigated in rotarod, antinociceptive tolerance, reward and gastrointestinal transit tests. KEY RESULTS BN-9 acted as a novel multifunctional agonist at mu, delta, kappa, NPFF1 and NPFF2 receptors in cAMP assays. In the tail-flick test, BN-9 produced dose-related antinociception and was approximately equipotent to morphine; this antinociception was blocked by mu and kappa receptor antagonists, but not by the d receptor antagonist. In the formalin test, supraspinal administration of BN-9 produced significant analgesia. Notably, repeated administration of BN-9 produced analgesia without loss of potency over 8 days. In contrast, repeated i.c.v. co-administration of BN-9 with the NPFF receptor antagonist RF9 produced significant antinociceptive tolerance. Furthermore, i.c.v. BN-9 induced conditioned place preference. When given by the same routes, BN-9 had a more than eightfold higher ED50 value for gastrointestinal transit inhibition compared with the ED50 values for antinociception. CONCLUSIONS AND IMPLICATIONS BN-9 produced a robust, nontolerance-forming analgesia with limited inhibition of gastrointestinal transit. As BN-9 is able to activate both opioid and NPFF systems, this provides an interesting approach for the development of novel analgesics with minimal side effects.
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opposite effects of neuropeptide ff on central antinociception induced by endomorphin 1 and endomorphin 2 in mice
PLOS ONE, 2014Co-Authors: Zilong Wang, Quan Fang, Zhenglan Han, Jiaxin Pan, Honghai Tang, Pei Wang, Ting Zheng, Xuemei Chang, Rui WangAbstract:Neuropeptide FF (NPFF) is known to be an endogenous opioid-modulating peptide. Nevertheless, very few researches focused on the interaction between NPFF and endogenous opioid peptides. In the present study, we have investigated the effects of NPFF system on the supraspinal antinociceptive effects induced by the endogenous µ-opioid receptor agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2). In the mouse tail-flick assay, intracerebroventricular injection of EM-1 induced antinociception via µ-opioid receptor while the antinociception of intracerebroventricular injected EM-2 was mediated by both µ- and κ-opioid receptors. In addition, central administration of NPFF significantly reduced EM-1-induced central antinociception, but enhanced EM-2-induced central antinociception. The results using the selective NPFF1 and NPFF2 receptor agonists indicated that the EM-1-modulating action of NPFF was mainly mediated by NPFF2 receptor, while NPFF potentiated EM-2-induecd antinociception via both NPFF1 and NPFF2 receptors. To further investigate the roles of µ- and κ-opioid systems in the opposite effects of NPFF on central antinociception of endomprphins, the µ- and κ-opioid receptors selective agonists DAMGO and U69593, respectively, were used. Our results showed that NPFF could reduce the central antinociception of DAMGO via NPFF2 receptor and enhance the central antinociception of U69593 via both NPFF1 and NPFF2 receptors. Taken together, our data demonstrate that NPFF exerts opposite effects on central antinociception of endomorphins and provide the first evidence that NPFF potentiate antinociception of EM-2, which might result from the interaction between NPFF and κ-opioid systems.
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Dose-related effects of i.c.v. administration of NPFF on the central antinociception of EM-1 (i.c.v.) (A) and EM-2 (i.c.v.) (B), in mouse tail-flick assays.
2014Co-Authors: Zilong Wang, Quan Fang, Zhenglan Han, Jiaxin Pan, Honghai Tang, Pei Wang, Ting Zheng, Xuemei ChangAbstract:(A) NPFF (3, 10 and 15 nmol) reduced 7.5 nmol EM-1-induced central antinociception. (B) NPFF (3, 10 and 15 nmol) potentiated 7.5 nmol EM-2-induced central antinociception. Each value represents mean ± S.E.M. (n = 7–12 mice/group). ***p
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The effects of i.c.v. administration of NPFF and related peptides on the central antinociception of U69593 (i.c.v.) in mouse tail-flick test.
2014Co-Authors: Zilong Wang, Quan Fang, Zhenglan Han, Jiaxin Pan, Honghai Tang, Pei Wang, Ting Zheng, Xuemei ChangAbstract:(A) Dose-related effects of NPFF (3, 10 and 15 nmol) on the central antinociception of U69593. (B) Co-administrated RF9 (15 nmol, i.c.v.) antagonized the modulatory effects of NPFF (15 nmol, i.c.v.) on the central antinociception of U69593 (i.c.v.). (C) The effects of NPVF and dNPA on the central antinociception of U69593. Each value represents mean ± S.E.M. (n = 7–8 mice/group). ***P
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pharmacological characterization of en 9 a novel chimeric peptide of endomorphin 2 and neuropeptide ff that produces potent antinociceptive activity and limited tolerance
Neuropharmacology, 2016Co-Authors: Zilong Wang, Quan Fang, Zhenglan Han, Honghai Tang, Pei Wang, Jing-jing Song, Ting Zhang, Run Zhang, Meng-na Zhang, Rui WangAbstract:Mounting evidences indicate the functional interactions between neuropeptide FF (NPFF) and opioids, including the endogenous opioids. In the present work, EN-9, a chimeric peptide containing the functional domains of the endogenous opioid endomorphin-2 (EM-2) and NPFF, was synthesized and pharmacologically characterized. In vitro cAMP assay demonstrated that EN-9 was a multifunctional agonist of κ-opioid, NPFF1 and NPFF2 receptors. In the mouse tail-flick test, intracerebroventricularly (i.c.v.) administration of EN-9 produced significant antinociception with an ED50 value of 13.44 nmol, which lasted longer than that of EM-2. In addition, EN-9 induced potent antinociception after both intravenous (i.v.) and subcutaneous (s.c.) injection. Furthermore, the experiments using the antagonists of opioid and NPFF receptors indicated that the central antinociception of EN-9 was mainly mediated by κ-opioid receptor, independently on NPFF receptors. Notably, the central antinociception of EN-9 was not reduced over a period of 6 days repeated i.c.v. injection. Repeated i.c.v. administration of EN-9 with the NPFF1 and NPFF2 receptors antagonist RF9 resulted in a progressive loss of analgesic potency, consistent with the development of tolerance. Moreover, central administration of EN-9 induced the place conditioning aversion only at a high dose of 60 nmol, but not at low doses. At supraspinal level, only high dose of EN-9 (60 nmol, i.c.v.) inhibited gastrointestinal transit via NPFF receptors. Similarly, systemic administration of EN-9 also inhibited gastrointestinal transit at high doses (10 and 30 mg/kg, i.v.). Taken together, the multifunctional agonist of κ-opioid and NPFF receptors EN-9 produced a potent, non-tolerance forming antinociception with limited side effects.
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bn 9 a chimeric peptide with mixed opioid and neuropeptide ff receptor agonistic properties produces nontolerance forming antinociception in mice
British Journal of Pharmacology, 2016Co-Authors: Zhenglan Han, Zilong Wang, Quan Fang, Yulong Sun, Jing-jing Song, Ting Zhang, Run Zhang, Meng-na Zhang, Yanhong Xing, Rui WangAbstract:BACKGROUND AND PURPOSE Neuropeptide FF (NPFF) behaves as an endogenous opioid-modulating peptide. In the present study, the opioid and NPFF pharmacophore-containing chimeric peptide BN-9 was synthesized and pharmacologically characterized. EXPERIMENTAL APPROACH Agonist activities of BN-9 at opioid and NPFF receptors were characterized in in vitro cAMP assays. Antinociceptive activities of BN-9 were evaluated in the mouse tail-flick and formalin tests. Furthermore, its side effects were investigated in rotarod, antinociceptive tolerance, reward and gastrointestinal transit tests. KEY RESULTS BN-9 acted as a novel multifunctional agonist at mu, delta, kappa, NPFF1 and NPFF2 receptors in cAMP assays. In the tail-flick test, BN-9 produced dose-related antinociception and was approximately equipotent to morphine; this antinociception was blocked by mu and kappa receptor antagonists, but not by the d receptor antagonist. In the formalin test, supraspinal administration of BN-9 produced significant analgesia. Notably, repeated administration of BN-9 produced analgesia without loss of potency over 8 days. In contrast, repeated i.c.v. co-administration of BN-9 with the NPFF receptor antagonist RF9 produced significant antinociceptive tolerance. Furthermore, i.c.v. BN-9 induced conditioned place preference. When given by the same routes, BN-9 had a more than eightfold higher ED50 value for gastrointestinal transit inhibition compared with the ED50 values for antinociception. CONCLUSIONS AND IMPLICATIONS BN-9 produced a robust, nontolerance-forming analgesia with limited inhibition of gastrointestinal transit. As BN-9 is able to activate both opioid and NPFF systems, this provides an interesting approach for the development of novel analgesics with minimal side effects.
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opposite effects of neuropeptide ff on central antinociception induced by endomorphin 1 and endomorphin 2 in mice
PLOS ONE, 2014Co-Authors: Zilong Wang, Quan Fang, Zhenglan Han, Jiaxin Pan, Honghai Tang, Pei Wang, Ting Zheng, Xuemei Chang, Rui WangAbstract:Neuropeptide FF (NPFF) is known to be an endogenous opioid-modulating peptide. Nevertheless, very few researches focused on the interaction between NPFF and endogenous opioid peptides. In the present study, we have investigated the effects of NPFF system on the supraspinal antinociceptive effects induced by the endogenous µ-opioid receptor agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2). In the mouse tail-flick assay, intracerebroventricular injection of EM-1 induced antinociception via µ-opioid receptor while the antinociception of intracerebroventricular injected EM-2 was mediated by both µ- and κ-opioid receptors. In addition, central administration of NPFF significantly reduced EM-1-induced central antinociception, but enhanced EM-2-induced central antinociception. The results using the selective NPFF1 and NPFF2 receptor agonists indicated that the EM-1-modulating action of NPFF was mainly mediated by NPFF2 receptor, while NPFF potentiated EM-2-induecd antinociception via both NPFF1 and NPFF2 receptors. To further investigate the roles of µ- and κ-opioid systems in the opposite effects of NPFF on central antinociception of endomprphins, the µ- and κ-opioid receptors selective agonists DAMGO and U69593, respectively, were used. Our results showed that NPFF could reduce the central antinociception of DAMGO via NPFF2 receptor and enhance the central antinociception of U69593 via both NPFF1 and NPFF2 receptors. Taken together, our data demonstrate that NPFF exerts opposite effects on central antinociception of endomorphins and provide the first evidence that NPFF potentiate antinociception of EM-2, which might result from the interaction between NPFF and κ-opioid systems.
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Dose-related effects of i.c.v. administration of NPFF on the central antinociception of EM-1 (i.c.v.) (A) and EM-2 (i.c.v.) (B), in mouse tail-flick assays.
2014Co-Authors: Zilong Wang, Quan Fang, Zhenglan Han, Jiaxin Pan, Honghai Tang, Pei Wang, Ting Zheng, Xuemei ChangAbstract:(A) NPFF (3, 10 and 15 nmol) reduced 7.5 nmol EM-1-induced central antinociception. (B) NPFF (3, 10 and 15 nmol) potentiated 7.5 nmol EM-2-induced central antinociception. Each value represents mean ± S.E.M. (n = 7–12 mice/group). ***p
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The effects of i.c.v. administration of NPFF and related peptides on the central antinociception of U69593 (i.c.v.) in mouse tail-flick test.
2014Co-Authors: Zilong Wang, Quan Fang, Zhenglan Han, Jiaxin Pan, Honghai Tang, Pei Wang, Ting Zheng, Xuemei ChangAbstract:(A) Dose-related effects of NPFF (3, 10 and 15 nmol) on the central antinociception of U69593. (B) Co-administrated RF9 (15 nmol, i.c.v.) antagonized the modulatory effects of NPFF (15 nmol, i.c.v.) on the central antinociception of U69593 (i.c.v.). (C) The effects of NPVF and dNPA on the central antinociception of U69593. Each value represents mean ± S.E.M. (n = 7–8 mice/group). ***P
