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Kornélia Tekes - One of the best experts on this subject based on the ideXlab platform.
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Effects of nociceptin and Nocistatin on uterine contraction.
Vitamins and hormones, 2015Co-Authors: Róbert Gáspár, Anna Klukovits, Beáta H Deák, Eszter Ducza, Kornélia TekesAbstract:The presence and effects of nociceptin (N/OFQ) and Nocistatin (NST) in the central nervous system have been reasonably well described, but less data are available on their peripheral functions. Besides their presence in several peripheral organs (white blood cells, airway, liver, skin, vascular and intestinal smooth muscles, ovary, and testis), they have been found in the pregnant myometrium in both rat and human. The level of their precursor prepronociceptin is elevated in the preterm human myometrium as compared with full-term samples, whereas it gradually increases toward term in the pregnant rat uterus. Both N/OFQ and NST inhibit myometrial contractions, an effect which can be enhanced by naloxone and blocked by Ca2 +-dependent K+ channel (BKCa) inhibitors. Both compounds increase the myometrial cAMP level which may be responsible for the activation of this channel and subsequent intracellular hyperpolarization. NST releases calcitonin gene-related peptide from the sensory nerve ends, which explains its cAMP-elevating effect. In contrast with the nervous system, where they behave as antagonists, N/OFQ and NST are able to potentiate the uterine-relaxing effect of each other in both rat and human tissues. Further studies are required to clarify the roles of N/OFQ and NST in the regulation of the myometrial contractions and the perception of pain during delivery.
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Nocistatin inhibits pregnant rat uterine contractions in vitro: roles of calcitonin gene-related peptide and calcium-dependent potassium channel.
European journal of pharmacology, 2013Co-Authors: Beáta H Deák, Kornélia Tekes, Anna Klukovits, Eszter Ducza, George Falkay, Róbert GáspárAbstract:The endogenous neuropeptide nociceptin/orphanin FQ, translated from the prepronociceptin gene, exerts a contraction-inhibitory effect on the rat uterus. As Nocistatin has been reported to cause functional antagonism of the pro-nociceptive effects of nociceptin, we set out to investigate its effects on the pregnant rat uterus and to elucidate its signalling pathway. The expression of prepronociceptin mRNA in the uterus and Nocistatin levels in the uterus and the plasma were confirmed by RT-PCR and radioimmunoassay. The uterine levels of prepronociceptin mRNA and Nocistatin were significantly increased by the last day of pregnancy, while the plasma Nocistatin levels remained unchanged. In the isolated organ bath studies Nocistatin inhibited the prostaglandin- and the KCl-evoked contractions in the uterus dose-dependently. This latter effect was decreased by preincubation with capsaicin. Incubation with calcitonin gene-related peptide after capsaicin treatment caused an elevation in the contraction-inhibitory effect of Nocistatin. The effect of Nocistatin was also decreased by the Ca(2+)-dependent K(+) channel inhibitor paxilline, against spontaneous uterine contractions. Nociceptin potentiated the action of Nocistatin. Naloxone decreased the effect of Nocistatin administered either alone or in combination with nociceptin. In Ca(2+)-poor environment, this effect of naloxone was suspended. Enzyme immunoassay for the uterine intracellular cAMP levels partially confirmed the results of in vitro contractility studies. We conclude that Nocistatin, generated locally in the uterus, exerts an inhibitory effect, the mechanism being mediated in part by Ca(2+)-dependent K(+) channels, the elevation of cAMP levels and sensory neuropeptides.
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Uterus-Relaxing Effects of Nociceptin and Nocistatin: Studies on Preterm and Term-Pregnant Human Myometrium In vitro
Reproductive System and Sexual Disorders, 2013Co-Authors: Beáta H Deák, Kornélia Tekes, Anna Klukovits, Eszter Ducza, Kormányos Z, Róbert GáspárAbstract:The endogenous neuropeptides nociceptin/orphanin FQ and Nocistatin translated from the prepronociceptin gene exert a relaxant effect on the rat uterus. Previous studies have reported their role in pain transmission in the central nervous system both in rodents and in humans, but to date only limited information is available on their effects in the periphery, and there are no data on their presence in the human uterus. The expression of prepronociceptin mRNA in the human uterus was confirmed by an RT-PCR technique. In vitro contractility studies of the action of nociceptin and Nocistatin on human uterine tissues were performed in an isolated organ system. Human myometrial strips from cesarean sections at full-term pregnancy and at preterm labor were stimulated with oxytocin, and the relaxant effects of nociceptin and Nocistatin were studied. The level of prepronociceptin mRNA was significantly decreased in full-term pregnant uterus samples as compared with preterm pregnancy samples. Nociceptin and Nocistatin significantly and dose-dependently inhibited the oxytocin evoked contractions in the human uterus. In the presence of Nocistatin, the uterus-relaxant effect of nociceptin was enhanced. In contrast, nociceptin did not alter the uterus-relaxant effect of Nocistatin. We conclude that locally generated nociceptin and Nocistatin both exert a relaxant effect on the human uterus, and Nocistatin can potentiate the relaxant effect of nociceptin, though for this to occur Nocistatin administration must precede the administration of nociceptin.
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Deciphering intracellular localization and physiological role of nociceptin and Nocistatin.
Peptides, 2013Co-Authors: Saeed Tariq, Kornélia Tekes, Syed M. Nurulain, Ernest AdeghateAbstract:Abstract Nociceptin and Nocistatin are endogenous ligands of G protein coupled receptor family. Numerous techniques have been used to study the diverse parameters including, localization, distribution and ultrastructure of these peptides. The majority of the study parameters are based on their physiological roles in different organ systems. The present study presents an overview of the different methods used for the study of nociceptin, Nocistatin and their receptors. Nociceptin has been implicated in many physiological functions including, nociception, locomotion, stressed-induced analgesia, learning and memory, neurotransmitter and hormone release, renal function, neuronal differentiation, sexual and reproductive behavior, uterine contraction, feeding, anxiety, gastrointestinal motility, cardiovascular function, micturition, cough, hypoxic–ischemic brain injury, diuresis and sodium balance, temperature regulation, vestibular function, and mucosal transport. It has been noted that the use of light and electron microscopy was less frequent, though it may be one of the most promising tools to study the intracellular localization of these neuropeptides. In addition, more studies on the level of circulating nociceptin and Nocistatin are also necessary for investigating their clinical roles in health and disease. A variety of modern tools including physiological, light and electron microscopy (EM) are needed to decipher the extent of intracellular localization, tissue distribution and function of these peptides. The intracellular localization of nociceptin and Nocistatin will require a high resolution transmission EM capable of identifying these peptides and other supporting molecules that co-localize with them. A tracing technique could also elucidate a possible migratory ability of nociceptin and Nocistatin from one cellular compartment to the other.
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Nocistatin and nociceptin given centrally induce opioid-mediated gastric mucosal protection.
Peptides, 2008Co-Authors: Zoltán S. Zádori, Kornélia Tekes, N Shujaa, László Köles, Kornél Király, K GyiresAbstract:Abstract Nociceptin (N/OFQ) and Nocistatin (NST) are two endogenous neuropeptides derived from the same precursor protein, preproN/OFQ. The aim of the present work was to study the effect of NST on the ethanol-induced mucosal damage compared with that of N/OFQ following intracerebroventricular (i.c.v.) administration in the rat and to analyze the mechanism of the gastroprotective action. It was found that both NST and N/OFQ reduced the mucosal lesions in the same dose range (0.2–1 nmol i.c.v.), but in higher doses (2–5 nmol i.c.v.) the gastroprotective effect of both peptides was highly diminished. The gastroprotective effect of N/OFQ (1 nmol), but not that of NST (1 nmol), was reduced by the selective nociceptin receptor antagonist J-113397 (69 nmol i.c.v.). Similarly, decrease of the gastroprotective effect was observed after the combination of NST (1 nmol) with N/OFQ (0.6 or 1 nmol). However, addition of the gastroprotective effects was observed, when lower dose (0.2 nmol) of NST was given prior to N/OFQ (0.6 nmol). The gastroprotective effect of both N/OFQ and NST was antagonized by naloxone (27 nmol), β-funaltrexamine (20 nmol), naltrindole (5 nmol) and norbinaltorphimine (14 nmol), the μ-, δ- and κ-opioid receptor antagonists, respectively, given i.c.v. The mucosal protection was significantly decreased after bilateral cervical vagotomy. The present findings suggest that NST similar to N/OFQ, may also induce gastric mucosal protective action initiated centrally in a vagal-dependent mechanism. Opioid component is likely to be involved in the gastroprotective effect of both NST and N/OFQ.
Shinro Tachibana - One of the best experts on this subject based on the ideXlab platform.
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elevated prepronociceptin nociceptin orphanin fq and Nocistatin concentrations in rat chronic constriction nerve injury and diabetic neuropathic pain models
Neuroscience Letters, 2012Co-Authors: Eugene H. Liu, Tat-leang Lee, Malathi Govindasamy, Hong Jye Neo, Chian Ming Low, Shinro TachibanaAbstract:Nociceptin/orphanin FQ (N/OFQ) and Nocistatin are derived from the same precursor peptide, prepronociceptin. N/OFQ and Nocistatin have been postulated to participate in pain modulation. In this study, we investigated whether the prepronociceptin, N/OFQ and Nocistatin concentrations in the brain and spinal cord would be altered in chronic constriction injury and diabetic rat neuropathic pain models. Total brain and spinal cord lysates as well as serum from rats that had undergone chronic constriction injury and streptozocin-induced diabetic neuropathy were used to determine the concentrations of three peptides using competitive radioimmunoassay. We found that N/OFQ and prepronociceptin concentrations were significantly raised in both rat neuropathic pain models. Nocistatin was raised in the brains of post traumatic neuropathy pain rats. Overall, our data have demonstrated for the first time that prepronociceptin, N/OFQ and Nocistatin concentrations are significantly altered at different tissues of two rat neuropathy pain models.
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Elevated prepronociceptin, nociceptin/orphanin FQ and Nocistatin concentrations in rat chronic constriction nerve injury and diabetic neuropathic pain models
Neuroscience letters, 2011Co-Authors: Eugene H. Liu, Tat-leang Lee, Malathi Govindasamy, Hong Jye Neo, Chian Ming Low, Shinro TachibanaAbstract:Nociceptin/orphanin FQ (N/OFQ) and Nocistatin are derived from the same precursor peptide, prepronociceptin. N/OFQ and Nocistatin have been postulated to participate in pain modulation. In this study, we investigated whether the prepronociceptin, N/OFQ and Nocistatin concentrations in the brain and spinal cord would be altered in chronic constriction injury and diabetic rat neuropathic pain models. Total brain and spinal cord lysates as well as serum from rats that had undergone chronic constriction injury and streptozocin-induced diabetic neuropathy were used to determine the concentrations of three peptides using competitive radioimmunoassay. We found that N/OFQ and prepronociceptin concentrations were significantly raised in both rat neuropathic pain models. Nocistatin was raised in the brains of post traumatic neuropathy pain rats. Overall, our data have demonstrated for the first time that prepronociceptin, N/OFQ and Nocistatin concentrations are significantly altered at different tissues of two rat neuropathy pain models.
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levels of neuropeptides Nocistatin nociceptin orphanin fq and their precursor protein in a rat neuropathic pain model
Peptides, 2007Co-Authors: Tessy Joseph, Yuji Nishiuchi, Terutoshi Kimura, Tat-leang Lee, Chiang Siau, Shinro TachibanaAbstract:Neuropeptides nociceptin/orphanin FQ (N/OFQ) and Nocistatin (NST) are related to pain modulation. The amounts of these peptides and their precursor protein, prepronociceptin (ppN/OFQ) in the brain, spinal cord and serum samples of rats with partial sciatic nerve ligation (PSNL) were compared with those in naive rats using radioimmunoassay (RIA). There was a significant rise in the levels of ppN/OFQ, N/OFQ and NST in the brains of PSNL rats. Their spinal cords showed significantly increased ppN/OFQ and NST levels but no change in N/OFQ levels. The PSNL rats also had increased serum NST (statistically significant) and N/OFQ (statistically insignificant) with decreased ppN/OFQ suggesting important roles of these peptides in neuropathic pain mechanism.
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Nocistatin attenuated the nociceptin induced c-Fos expression in the mouse hippocampus.
Neuropeptides, 2007Co-Authors: Jamil Ahsan Kazi, Tat-leang Lee, E. H. C. Liu, Shinro TachibanaAbstract:Nocistatin and nociceptin/orphaninFQ (N/OFQ) are the two new peptides which may have roles in nociception, memory, anxiety, and other biological functions. Nocistatin acts as a functional antagonist to N/OFQ in several functions, but their neuro-anatomical sites of interaction are unknown. We investigated the effect of combined intracerebroventricular (i.c.v.) injection of Nocistatin with N/OFQ, on N/OFQ induced c-Fos expression in the mouse hippocampus, using c-Fos immunohistochemistry. We found that co-injection of Nocistatin with N/OFQ significantly attenuated N/OFQ induced c-Fos expression in the hippocampus.
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Localization of Nocistatin-binding sites in mice brain and spinal cord using a biotinylated Nocistatin probe.
Neuroreport, 2007Co-Authors: Jamil Ahsan Kazi, Tat-leang Lee, E. H. C. Liu, Shinro TachibanaAbstract:Nocistatin and nociceptin/orphanin FQ are two neuropeptides processed from the same precursor prepronociceptin. They have opposing roles in nociception and several other biological functions. Whereas the location and structure of the nociceptin/orphanin FQ receptors has been defined, the location of the Nocistatin receptors remains unknown. In the course of this study, we synthesized a novel probe for histochemistry by linking biotin to the N terminus of Nocistatin, and purified this with high-pressure liquid chromatography and confirmed the structure by mass spectrometer. Using this probe, we found Nocistatin-binding sites in the cerebral cortex and the dorsal horn nucleus of the spinal cord. We also found that the Nocistatin-binding sites were in the cell body, whereas the nociceptin/orphanin FQ binding sites were on the fibrous processes.
Seiji Ito - One of the best experts on this subject based on the ideXlab platform.
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Development of a novel photoaffinity probe for labeling Nocistatin receptor.
Biochemical and biophysical research communications, 2018Co-Authors: Masashi Harada, Seiji Ito, Toshiaki Minami, Emiko Okuda-ashitakaAbstract:Abstract Nocistatin (NST) is a neuropeptide produced from the same precursor protein of opioid peptide nociceptin/orphanin FQ, and it is involved in a broad range of central functions including pain transmission in the nervous system. However, the composition and structure of the receptor(s) for NST remain unclear. Here, we developed NST photoaffinity probe to identify NST receptor. The NST photoaffinity probe contains an azide moiety for the tagging of the binding protein as well as biotin for protein detection. Intrathecal administration of a NST photoaffinity probe, biotin-(AC5)2-[Y6,azF14]bNST, inhibited the nociceptin/orphanin FQ-evoked tactile pain allodynia in a manner similar to that of NST. The biotin-(AC5)2-[Y6,azF14]bNST-binding proteins were primarily localized in the gray matter of the spinal cord. After photo-crosslinking of the protein complex with biotin-(AC5)2-[Y6,azF14]bNST, two dominant binding protein bands were observed at 58 and 64 kDa. Thus, biotin-(AC5)2-[Y6,azF14]bNST has pharmacological activity and is useful for characterizing the NST receptor.
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Pain regulation by Nocistatin-targeting molecules: G protein-coupled-receptor and Nocistatin-interacting protein.
Vitamins and hormones, 2015Co-Authors: Emiko Okuda-ashitaka, Seiji ItoAbstract:Nociceptin/orphanin FQ (N/OFQ) and Nocistatin (NST) are neuropeptides produced from the same precursor protein. N/OFQ is involved in a broad range of central functions including pain, learning, memory, anxiety, and feeding. However, NST has opposite effects on various central functions evoked by N/OFQ. The regulation of their receptors may be important for these opposite functions of NST and N/OFQ. Although N/OFQ binds to a specific N/OFQ receptor, the target molecule of NST remains unclear. Some biological effects of NST are mediated by a G protein-coupled receptor. Furthermore, using high-performance affinity nanobeads, we recently identified a 4-nitrophenylphosphatase domain and nonneuronal SNAP25-like protein homolog 1 (NIPSNAP1) as a protein that interacts with NST in the mouse spinal cord. The inhibition of N/OFQ-evoked tactile pain allodynia by NST is mediated by NIPSNAP1. This review focuses on the molecular mechanisms of pain regulation by the target molecules of NST including a G protein-coupled receptor and NIPSNAP1.
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Nocistatin: milestone of one decade of research.
Current pharmaceutical design, 2014Co-Authors: Emiko Okuda-ashitaka, Seiji ItoAbstract:A neuropeptide nociceptin or orphanin FQ (N/OFQ) is an endogenous ligand for the orphan opioid receptor-like receptor. During studies on the analysis of the precursor of N/OFQ, we identified a novel neuropeptide produced from the same precursor and named it "Nocistatin (NST)". Intrathecal (i.t.) administration of N/OFQ induces pain responses including touch-evoked allodynia and thermal hyperalgesia, and simultaneous administration of NST blocks the allodynia and hyperalgesia induced by N/OFQ. In the years since these discoveries, N/OFQ has been shown to be involved in a wide range of pharmacological activities, such as relaying pain perception in peripheral tissues, to the central nervous system, and NST was shown to have opposite effects on various central functions evoked by N/OFQ. Pharmacological characterization using various neurotransmitter agents, agonists, antagonists and knockout mice in vivo; electrophysiological and immunohistological analysis ex vivo; and molecular cloning using affinity chromatography of high-performance affinity nanobeads; and protein processing measurement using bioluminescence resonance energy transfer (BRET) in vitro have generated new insights into pain transmission regulated by NST and N/OFQ. This review focuses on the molecular and cellular mechanisms of pain transmission regulated by NST.
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Identification of NIPSNAP1 as a Nocistatin-interacting Protein Involving Pain Transmission
The Journal of biological chemistry, 2012Co-Authors: Emiko Okuda-ashitaka, Toshiaki Minami, Shingo Tsubouchi, Hiroshi Kiyonari, Akihiro Iwamatsu, Tetsuo Noda, Hiroshi Handa, Seiji ItoAbstract:4-Nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) is a molecule of physiologically unknown function, although it is predominantly expressed in the brain, spinal cord, liver, and kidney. We identified NIPSNAP1 as a protein that interacts with the neuropeptide Nocistatin (NST) from synaptosomal membranes of mouse spinal cord using high-performance affinity latex beads. NST, which is produced from the same precursor protein as an opioid-like neuropeptide nociceptin/orphanin FQ (N/OFQ), has opposite effects on pain transmission evoked by N/OFQ. The calculated full-length pre-protein of NIPSNAP1 was 33 kDa, whereas the N-terminal truncated form of NIPSNAP1 (29 kDa) was ubiquitously expressed in the neuronal tissues, especially in synaptic membrane and mitochondria of brain. The 29-kDa NIPSNAP1 was distributed on the cell surface, and NST interacted with the 29-kDa but not the 33-kDa NIPSNAP1. Although intrathecal injection of N/OFQ induced tactile allodynia in both wild-type and NIPSNAP1-deficient mice, the inhibition of N/OFQ-evoked tactile allodynia by NST seen in wild-type mice was completely lacking in the deficient mice. These results suggest that NIPSNAP1 is an interacting molecule of NST and plays a crucial role in pain transmission.
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Monitoring for dynamic biological processing by intramolecular bioluminescence resonance energy transfer system using secreted luciferase.
Analytical biochemistry, 2004Co-Authors: Tomomi Otsuji, Emiko Okuda-ashitaka, Seiji Ito, Satoshi Kojima, Hidefumi Akiyama, Yoshihiro OhmiyaAbstract:Abstract Proteolytic processing plays crucial roles in physiological and pathophysiological cellular functions such as peptide generation, cell cycle, and apoptosis. We developed a novel biophysical bioluminescence resonance energy transfer (BRET) system between a secreted Vargula luciferase (Vluc) and an enhanced yellow fluorescent protein (EYFP) for visualization of cell biological processes. The bioluminescence spectrum of the fusion protein (Vluc–EYFP) is bimodal ( λ max =460 nm (Vluc) and 525 nm (EYFP)), indicating that the excited-state energy of Vluc transfers to EYFP (in short, BRET). The BRET signal can be measured in the culture medium and pursue quantitative production of two neuropeptides, Nocistatin (NST) and nociceptin/orphanin FQ (N/OFQ) in living cells. NST and N/OFQ are located in tandem on the same precursor, but NST exhibits antagonistic action against N/OFQ-induced central functions. Insertion of a portion of the NST–N/OFQ precursor (Glu-Gln-Lys-Gln-Leu-Gln-Lys-Arg-Phe-Gly-Gly-Phe-Tyr-Gly) in Vluc–EYFP makes the fusion protein cleavable at Lys-Arg in NG108-15 cells, and proprotein convertase 1 enhances this digestion. The change in BRET signals quantifies the processing of the fusion protein. Our novel intramolecular BRET system using a secreted luciferase is useful for investigating peptide processing in living cells.
Seifollah Ahmadi - One of the best experts on this subject based on the ideXlab platform.
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Selective Suppression of Inhibitory Synaptic Transmission by Nocistatin in the Rat Spinal Cord Dorsal Horn
2013Co-Authors: H. Ulrich Zeilhofer, Uta Muth-selbach, Hans Gühring, Katharina Erb, Seifollah AhmadiAbstract:Nociceptin/orphanin FQ (N/OFQ) and Nocistatin (NST) are two recently identified neuropeptides with opposing effects on several CNS functions, including spinal nociception. The cellular mechanisms that underlie this antagonism are not known. Here, we have investigated the effects of both peptides on synaptic transmission mediated by the three fast neurotransmitters L-glutamate, glycine, and GABA in the superficial layers of the rat spinal cord horn, which constitute the first important site of integration of nociceptive information in the pain pathway. NST selectively reduced transmitter release from inhibitory interneurons via a presynaptic Bordetella pertussis toxin-sensitive mechanism but left excitatory glutamatergic transmission unaffected. In contrast, N/OFQ only inhibited excitatory transmission. In the rat formalin test, an animal model of tonic pain in which N/OFQ exerts antinociceptive activity, NST induced profoun
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The role of the ORL1 receptor in the modulation of spinal neurotransmission by nociceptin/orphanin FQ and Nocistatin.
European journal of pharmacology, 2001Co-Authors: Seifollah Ahmadi, Jörg T. Liebel, H. Ulrich ZeilhoferAbstract:Nociceptin/orphanin FQ and Nocistatin are two neuropeptides with opposing effects on spinal neurotransmission and nociception. Nociceptin/orphanin FQ selectively suppresses excitatory glutamatergic neurotransmission, while Nocistatin selectively interferes with glycinergic and gamma-aminobutyric acid (GABA)-ergic transmission. Here, we performed whole-cell patch-clamp recordings from superficial rat spinal cord dorsal horn neurons to investigate the role of the opioid receptor-like (ORL)1 receptor for modulatory actions of these peptides. The partial ORL1 receptor antagonist [phe1psi(CH(2)-NH)Gly(2)]nociceptin-(1-13)NH(2) competitively reversed the effects of nociceptin/orphanin FQ on excitatory neurotransmission (estimated pA(2) 6.43), but left the suppression of inhibitory synaptic transmission by Nocistatin unaffected. These results indicate that the inhibitory action of nociceptin/orphanin FQ on glutamatergic transmission is mediated via ORL1 receptors, while Nocistatin acts via a different so far unidentified receptor.
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the role of the orl1 receptor in the modulation of spinal neurotransmission by nociceptin orphanin fq and Nocistatin
European Journal of Pharmacology, 2001Co-Authors: Seifollah Ahmadi, Jörg T. Liebel, Ulrich H ZeilhoferAbstract:Nociceptin/orphanin FQ and Nocistatin are two neuropeptides with opposing effects on spinal neurotransmission and nociception. Nociceptin/orphanin FQ selectively suppresses excitatory glutamatergic neurotransmission, while Nocistatin selectively interferes with glycinergic and gamma-aminobutyric acid (GABA)-ergic transmission. Here, we performed whole-cell patch-clamp recordings from superficial rat spinal cord dorsal horn neurons to investigate the role of the opioid receptor-like (ORL)1 receptor for modulatory actions of these peptides. The partial ORL1 receptor antagonist [phe1psi(CH(2)-NH)Gly(2)]nociceptin-(1-13)NH(2) competitively reversed the effects of nociceptin/orphanin FQ on excitatory neurotransmission (estimated pA(2) 6.43), but left the suppression of inhibitory synaptic transmission by Nocistatin unaffected. These results indicate that the inhibitory action of nociceptin/orphanin FQ on glutamatergic transmission is mediated via ORL1 receptors, while Nocistatin acts via a different so far unidentified receptor.
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Selective suppression of inhibitory synaptic transmission by Nocistatin in the rat spinal cord dorsal horn.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000Co-Authors: H. Ulrich Zeilhofer, Hans Gühring, Katharina Erb, Uta Muth Selbach, Seifollah AhmadiAbstract:Nociceptin/orphanin FQ (N/OFQ) and Nocistatin (NST) are two recently identified neuropeptides with opposing effects on several CNS functions, including spinal nociception. The cellular mechanisms that underlie this antagonism are not known. Here, we have investigated the effects of both peptides on synaptic transmission mediated by the three fast neurotransmitters l-glutamate, glycine, and GABA in the superficial layers of the rat spinal cord horn, which constitute the first important site of integration of nociceptive information in the pain pathway. NST selectively reduced transmitter release from inhibitory interneurons via a presynaptic Bordetella pertussis toxin-sensitive mechanism but left excitatory glutamatergic transmission unaffected. In contrast, N/OFQ only inhibited excitatory transmission. In the rat formalin test, an animal model of tonic pain in which N/OFQ exerts antinociceptive activity, NST induced profound hyperalgesia after intrathecal application. Similar to glycine and GABA(A) receptor antagonists, NST had no significant effects in the rat tail-flick test, a model of acute thermal pain. Our results provide a cellular basis for the antagonism of N/OFQ and NST and suggest the existence of a so far unidentified membrane receptor for NST. In addition, they support a role of NST as an endogenous inhibitor of glycinergic and GABAergic neurotransmission in the sensory part of the spinal cord and as a mediator of spinal hyperalgesia.
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Modulation of Synaptic Transmission by Nociceptin/Orphanin FQ and Nocistatin in the Spinal Cord Dorsal Horn of Mutant Mice Lacking the Nociceptin/Orphanin FQ Receptor
2000Co-Authors: Seifollah Ahmadi, Carolin Kotalla, Hiroshi Takeshima, Andreas PahlAbstract:Nociceptin/orphanin FQ (N/OFQ) and Nocistatin (NST) are two neuropeptides derived from the same precursor protein that exhibit opposing effects on spinal neurotransmission and no-ciception. Here, we have used whole-cell, patch-clamp record-ings from visually identified neurons in spinal cord dorsal horn slices of genetically modified mice to investigate the role of the N/OFQ receptor (N/OFQ-R) in the modulatory action of both peptides on excitatory glutamatergic and inhibitory glycinergic and g-aminobutyric acid (GABA)-ergic synaptic transmission. In wild-type mice, N/OFQ selectively suppressed excitatory trans-mission in a concentration-dependent manner but left inhibitory synaptic transmission unaffected. In contrast, NST reduced only inhibitory but not a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated excitatory synapti
H. Ulrich Zeilhofer - One of the best experts on this subject based on the ideXlab platform.
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Selective Suppression of Inhibitory Synaptic Transmission by Nocistatin in the Rat Spinal Cord Dorsal Horn
2013Co-Authors: H. Ulrich Zeilhofer, Uta Muth-selbach, Hans Gühring, Katharina Erb, Seifollah AhmadiAbstract:Nociceptin/orphanin FQ (N/OFQ) and Nocistatin (NST) are two recently identified neuropeptides with opposing effects on several CNS functions, including spinal nociception. The cellular mechanisms that underlie this antagonism are not known. Here, we have investigated the effects of both peptides on synaptic transmission mediated by the three fast neurotransmitters L-glutamate, glycine, and GABA in the superficial layers of the rat spinal cord horn, which constitute the first important site of integration of nociceptive information in the pain pathway. NST selectively reduced transmitter release from inhibitory interneurons via a presynaptic Bordetella pertussis toxin-sensitive mechanism but left excitatory glutamatergic transmission unaffected. In contrast, N/OFQ only inhibited excitatory transmission. In the rat formalin test, an animal model of tonic pain in which N/OFQ exerts antinociceptive activity, NST induced profoun
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The Spinal Antinociceptive Effect of Nocistatin in Neuropathic Rats Is Blocked by D-Serine
Anesthesiology, 2004Co-Authors: Uta Muth-selbach, Eva Dybek, Katrin Kollosche, Jens-ulrich Stegmann, Holger Holthusen, Peter Lipfert, H. Ulrich ZeilhoferAbstract:Background: The neuropeptide Nocistatin (NST) has been implicated in the modulation of nociceptive responses in the spinal cord. Depending on the dose, both pronociceptive and antinociceptive effects have repeatedly been reported. The pronociceptive effect is most likely attributable to inhibition of synaptic glycine and -aminobutyric acid release and a subsequent reduction in the activation of inhibitory glycine and -aminobutyric acid receptors, but the mechanisms of its antinociceptive action have hitherto remained elusive. It has recently been demonstrated that synaptically released glycine contributes to N-methyl-D-aspartate receptor activation. The authors therefore investigated whether a reduction in glycine release might also account for the antinociceptive action of NST in neuropathic rats. Methods: The authors analyzed the effects of spinally applied NST in the chronic constriction injury model of neuropathic pain. NST was injected intrathecally from nanomolar to picomolar doses and its effects on thermal paw withdrawal latencies were monitored. Furthermore, we tested whether D-serine (100 g per rat), a full agonist at the glycine binding site of the N-methyl-D-aspartate receptor, would interfere with the effects of NST. Results: At high doses (10 nmol/rat), intrathecally injected NST was pronociceptive, whereas lower doses (1 pmol/rat) elicited antinociception. The antinociceptive, but not the pronociceptive, action was occluded by intrathecal pretreatment with D-serine. L-serine, which does not bind to N-methyl-D-aspartate receptors, affected neither the pronociceptive nor the antinociceptive effect. Conclusions: These results demonstrate that NST produces a biphasic dose-dependent effect on neuropathic pain. The spinal antinociception by NST is most likely attributable to inhibition of glycine-dependent N-methyl-D-aspartate receptor activation.
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The role of the ORL1 receptor in the modulation of spinal neurotransmission by nociceptin/orphanin FQ and Nocistatin.
European journal of pharmacology, 2001Co-Authors: Seifollah Ahmadi, Jörg T. Liebel, H. Ulrich ZeilhoferAbstract:Nociceptin/orphanin FQ and Nocistatin are two neuropeptides with opposing effects on spinal neurotransmission and nociception. Nociceptin/orphanin FQ selectively suppresses excitatory glutamatergic neurotransmission, while Nocistatin selectively interferes with glycinergic and gamma-aminobutyric acid (GABA)-ergic transmission. Here, we performed whole-cell patch-clamp recordings from superficial rat spinal cord dorsal horn neurons to investigate the role of the opioid receptor-like (ORL)1 receptor for modulatory actions of these peptides. The partial ORL1 receptor antagonist [phe1psi(CH(2)-NH)Gly(2)]nociceptin-(1-13)NH(2) competitively reversed the effects of nociceptin/orphanin FQ on excitatory neurotransmission (estimated pA(2) 6.43), but left the suppression of inhibitory synaptic transmission by Nocistatin unaffected. These results indicate that the inhibitory action of nociceptin/orphanin FQ on glutamatergic transmission is mediated via ORL1 receptors, while Nocistatin acts via a different so far unidentified receptor.
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Selective suppression of inhibitory synaptic transmission by Nocistatin in the rat spinal cord dorsal horn.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000Co-Authors: H. Ulrich Zeilhofer, Hans Gühring, Katharina Erb, Uta Muth Selbach, Seifollah AhmadiAbstract:Nociceptin/orphanin FQ (N/OFQ) and Nocistatin (NST) are two recently identified neuropeptides with opposing effects on several CNS functions, including spinal nociception. The cellular mechanisms that underlie this antagonism are not known. Here, we have investigated the effects of both peptides on synaptic transmission mediated by the three fast neurotransmitters l-glutamate, glycine, and GABA in the superficial layers of the rat spinal cord horn, which constitute the first important site of integration of nociceptive information in the pain pathway. NST selectively reduced transmitter release from inhibitory interneurons via a presynaptic Bordetella pertussis toxin-sensitive mechanism but left excitatory glutamatergic transmission unaffected. In contrast, N/OFQ only inhibited excitatory transmission. In the rat formalin test, an animal model of tonic pain in which N/OFQ exerts antinociceptive activity, NST induced profound hyperalgesia after intrathecal application. Similar to glycine and GABA(A) receptor antagonists, NST had no significant effects in the rat tail-flick test, a model of acute thermal pain. Our results provide a cellular basis for the antagonism of N/OFQ and NST and suggest the existence of a so far unidentified membrane receptor for NST. In addition, they support a role of NST as an endogenous inhibitor of glycinergic and GABAergic neurotransmission in the sensory part of the spinal cord and as a mediator of spinal hyperalgesia.