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https://www.readbyqxmd.com/read/29102248/nociceptin-and-the-nop-receptor-in-aversive-learning-in-mice
#1
Abdu Adem, Nather Madjid, Ulrika Kahl, Sarah Holst, Bassem Sadek, Johan Sandin, Lars Terenius, Sven Ove Ögren
The endogenous neuropeptide nociceptin (N/OFQ), which mediates its actions via the nociceptin receptor (NOP), is implicated in multiple behavioural and physiological functions. This study examined the effects of the NOP agonists N/OFQ and the synthetic agonist Ro 64-6198, the antagonists NNN and NalBzoH, as well as deletion of the Pronociceptin gene on emotional memory in mice. The animals were tested in the passive avoidance (PA) task, dependent on hippocampal and amygdala functions. N/OFQ injected intraventricularly (i...
October 25, 2017: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29071457/evaluation-of-cebranopadol-a-dually-acting-nociceptin-orphanin-fq-and-opioid-receptor-agonist-in-mouse-models-of-acute-tonic-and-chemotherapy-induced-neuropathic-pain
#2
Kinga Sałat, Anna Furgała, Robert Sałat
BACKGROUND: Cebranopadol (a.k.a. GRT-6005) is a dually acting nociceptin/orphanin FQ and opioid receptor agonist that has been recently developed in Phase 2 clinical trials for painful diabetic neuropathy or cancer pain. It also showed analgesic properties in various rat models of pain and had a better safety profile as compared to equi-analgesic doses of morphine. Since antinociceptive properties of cebranopadol have been studied mainly in rat models, in the present study, we assessed analgesic activity of subcutaneous cebranopadol (10 mg/kg) in various mouse pain models...
October 25, 2017: Inflammopharmacology
https://www.readbyqxmd.com/read/29038479/probing-ligand-recognition-of-the-opioid-pan-antagonist-at-076-at-nociceptin-kappa-mu-and-delta-opioid-receptors-through-structure-activity-relationships
#3
V Blair Journigan, Willma E Polgar, Edward W Tuan, James Lu, Pankaj R Daga, Nurulain T Zaveri
Few opioid ligands binding to the three classic opioid receptor subtypes, mu, kappa and delta, have high affinity at the fourth opioid receptor, the nociceptin/orphanin FQ receptor (NOP). We recently reported the discovery of AT-076 (1), (R)-7-hydroxy-N-((S)-1-(4-(3-hydroxyphenyl)piperidin-1-yl)-3-methylbutan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, a pan antagonist with nanomolar affinity for all four subtypes. Since AT-076 binds with high affinity at all four subtypes, we conducted a structure-activity relationship (SAR) study to probe ligand recognition features important for pan opioid receptor activity, using chemical modifications of key pharmacophoric groups...
October 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29038035/biochemical-and-pharmacological-characterization-of-three-opioid-nociceptin-hybrid-peptide-ligands-reveals-substantially-differing-modes-of-their-actions
#4
Anna I Erdei, Adina Borbély, Anna Magyar, Nóra Taricska, András Perczel, Ottó Zsíros, Győző Garab, Edina Szűcs, Ferenc Ötvös, Ferenc Zádor, Mihály Balogh, Mahmoud Al-Khrasani, Sándor Benyhe
In an attempt to design opioid-nociceptin hybrid peptides, three novel bivalent ligands, H-YGGFGGGRYYRIK-NH2, H-YGGFRYYRIK-NH2 and Ac-RYYRIKGGGYGGFL-OH were synthesized and studied by biochemical, pharmacological, biophysical and molecular modelling tools. These chimeric molecules consist of YGGF sequence, a crucial motif in the N-terminus of natural opioid peptides, and Ac-RYYRIK-NH2, which was isolated from a combinatorial peptide library as an antagonist or partial agonist that inhibits the biological activity of the endogenously occurring heptadecapeptide nociceptin...
October 13, 2017: Peptides
https://www.readbyqxmd.com/read/29031796/peptide-welding-technology-a-simple-strategy-for-generating-innovative-ligands-for-g-protein-coupled-receptors
#5
REVIEW
Girolamo Calo, Anna Rizzi, Chiara Ruzza, Federica Ferrari, Salvatore Pacifico, Elaine C Gavioli, Severo Salvadori, Remo Guerrini
Based on their high selectivity of action and low toxicity, naturally occurring peptides have great potential in terms of drug development. However, the pharmacokinetic properties of peptides, in particular their half life, are poor. Among different strategies developed for reducing susceptibility to peptidases, and thus increasing the duration of action of peptides, the generation of branched peptides has been described. However, the synthesis and purification of branched peptides is extremely complicated thus limiting their druggability...
October 12, 2017: Peptides
https://www.readbyqxmd.com/read/28944554/limited-potential-of-cebranopadol-to-produce-opioid-type-physical-dependence-in-rodents
#6
Thomas M Tzschentke, Babette Y Kögel, Stefanie Frosch, Klaus Linz
Cebranopadol is a novel potent analgesic agonist at the nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors. As NOP receptor activation has been shown to reduce side effects related to the activation of μ-opioid peptide (MOP) receptors, the present study evaluated opioid-type physical dependence produced by cebranopadol in mice and rats. In a naloxone-precipitated withdrawal assay in mice, a regimen of seven escalating doses of cebranopadol over 2 days produced only very limited physical dependence as evidenced by very little withdrawal symptoms (jumping) even at cebranopadol doses clearly exceeding the analgesic dose range...
September 25, 2017: Addiction Biology
https://www.readbyqxmd.com/read/28906039/novel-role-of-the-nociceptin-system-as-a-regulator-of-glutamate-transporter-expression-in-developing-astrocytes
#7
Logan C Meyer, Caitlin E Paisley, Esraa Mohamed, John W Bigbee, Tomasz Kordula, Hope Richard, Kabirullah Lutfy, Carmen Sato-Bigbee
Our previous results showed that oligodendrocyte development is regulated by both nociceptin and its G-protein coupled receptor, the nociceptin/orphanin FQ receptor (NOR). The present in vitro and in vivo findings show that nociceptin plays a crucial conserved role regulating the levels of the glutamate/aspartate transporter GLAST/EAAT1 in both human and rodent brain astrocytes. This nociceptin-mediated response takes place during a critical developmental window that coincides with the early stages of astrocyte maturation...
September 14, 2017: Glia
https://www.readbyqxmd.com/read/28856406/panicolytic-like-effects-caused-by-substantia-nigra-pars-reticulata-pretreatment-with-low-doses-of-endomorphin-1-and-high-doses-of-ctop-or-the-nop-receptors-antagonist-jtc-801-in-male-rattus-norvegicus
#8
Juliana Almeida da Silva, Audrey Franceschi Biagioni, Rafael Carvalho Almada, Renato Leonardo de Freitas, Norberto Cysne Coimbra
RATIONALE: Gamma-aminobutyric acid (GABA)ergic neurons of the substantia nigra pars reticulata (SNpr) are connected to the deep layers of the superior colliculus (dlSC). The dlSC, in turn, connect with the SNpr through opioid projections. Nociceptin/orphanin FQ peptide (N/OFQ) is a natural ligand of a Gi protein-coupled nociceptin receptor (ORL1; NOP) that is also found in the SNpr. Our hypothesis is that tectonigral opioid pathways and intranigral orphanin-mediated mechanisms modulate GABAergic nigrotectal connections...
August 30, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28805972/in-vitro-pharmacological-characterization-of-a-novel-unbiased-nop-receptor-selective-nonpeptide-agonist-at-403
#9
Federica Ferrari, Davide Malfacini, Blair V Journigan, Mark F Bird, Claudio Trapella, Remo Guerrini, David G Lambert, Girolamo Calo', Nurulain T Zaveri
Nociceptin/orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP), a member of the opioid receptor family. We recently identified a new high affinity and highly selective NOP agonist AT-403. In this study, we characterized the functional profile of AT-403 and compared it to other known nonpeptide NOP agonists Ro 65-6570, Ro 2q, SCH-221510, MCOPPB, AT-202 and SCH-486757, using the following assays: GTPγ[(35) S] stimulated binding, calcium mobilization assay in cells-expressing human NOP or classical opioid receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, and the electrically stimulated mouse vas deferens bioassay...
August 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28711193/nociceptin-receptors-in-alcohol-use-disorders-a%C3%A2-positron-emission-tomography-study-using-11-c-nop-1a
#10
Rajesh Narendran, Roberto Ciccocioppo, Brian Lopresti, Jennifer Paris, Michael L Himes, N Scott Mason
BACKGROUND: The neuropeptide transmitter nociceptin, which binds to the nociceptin/orphanin FQ peptide (NOP) receptor, is a core component of the brain's antistress system. Nociceptin exerts its antistress effect by counteracting the functions of corticotropin-releasing factor, the primary stress-mediating neuropeptide in the brain. Basic investigations support a role for medications that target nociceptin receptors in the treatment of alcohol use disorders. Thus, it is of high interest to measure the in vivo status of NOP receptors in individuals with alcohol use disorders...
May 31, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28705439/activation-of-nociceptin-orphanin-fq-receptors-inhibits-contextual-fear-memory-reconsolidation
#11
Khaoula Rekik, Raquel Faria Da Silva, Morgane Colom, Salvatore Pacifico, Nurulain T Zaveri, Girolamo Calo', Claire Rampon, Bernard Frances, Lionel Mouledous
Several neuropeptidergic systems act as modulators of cognitive performances. Among them, nociceptin, an opioid-like peptide also known as orphanin FQ (N/OFQ), has recently gained attention. Stimulation of its receptor, the N/OFQ opioid receptor (NOP), which is expressed in brain regions involved in emotion, memory and stress response, has inhibitory effects on the acquisition and/or consolidation of spatial and emotional memory in rodents. Recently, N/OFQ was also proposed to be linked to the pathogenesis of Post-Traumatic Stress Disorder in humans...
July 10, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28704271/mitigation-of-adverse-behavioral-impact-from-predator-exposure-by-the-nociceptin-orphanin-fq-peptide-antagonist-j-113397-in-rats
#12
Raymond F Genovese, Stefania Dobre
The nociceptin/orphanin FQ peptide (NOP) receptor is believed to have an integral modulatory function in the stress response system. We evaluated the highly selective NOP antagonist J-113397 (7.5 and 20.0 mg/kg), using a predator exposure in which rats were exposed to predator cats as a stressor. A single dose of J-113397 or vehicle was administered (intraperitoneally) shortly before exposure to the predators or a sham exposure. Behavioral impact was measured using elevated plus maze (EPM), open field activity (OFA), and an olfactory discrimination (OD)...
July 12, 2017: Behavioural Pharmacology
https://www.readbyqxmd.com/read/28697954/antinociceptive-action-of-nop-and-opioid-receptor-agonists-in-the-mouse-orofacial-formalin-test
#13
A Rizzi, C Ruzza, S Bianco, C Trapella, G Calo'
Nociceptin/orphanin FQ (N/OFQ) modulates several biological functions, including pain transmission via selective activation of a specific receptor named NOP. The aim of this study was the investigation of the antinociceptive properties of NOP agonists and their interaction with opioids in the trigeminal territory. The orofacial formalin (OFF) test in mice was used to investigate the antinociceptive potential associated to the activation of NOP and opioid receptors. Mice subjected to OFF test displayed the typical biphasic nociceptive response and sensitivity to opioid and NSAID drugs...
August 2017: Peptides
https://www.readbyqxmd.com/read/28645915/cebranopadol-blocks-the-escalation-of-cocaine-intake-and-conditioned-reinstatement-of-cocaine-seeking-in-rats
#14
Giordano de Guglielmo, Alessandra Matzeu, Jenni Kononoff, Julia Mattioni, Rémi Martin-Fardon, Olivier George
Cebranopadol is a novel agonist of nociceptin/orphanin FQ peptide (NOP) and opioid receptors with analgesic properties that is being evaluated in clinical Phase 2 and Phase 3 trials for the treatment of chronic and acute pain. Recent evidence indicates that the combination of opioid and NOP receptor agonism may be a new treatment strategy for cocaine addiction. We sought to extend these findings by examining the effects of cebranopadol on cocaine self-administration (0.5 mg/kg/infusion) and cocaine conditioned reinstatement in rats with extended access to cocaine...
September 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28644196/cebranopadol-a-novel-first-in-class-analgesic-drug-candidate-first-experience-in-patients-with-chronic-low-back-pain-in-a-randomized-clinical-trial
#15
Annette Christoph, Marie-Henriette Eerdekens, Maurits Kok, Gisela Volkers, Rainer Freynhagen
Chronic low back pain (LBP) is a common condition, usually with the involvement of nociceptive and neuropathic pain components, high economic burden and impact on quality of life. Cebranopadol is a potent, first-in-class drug candidate with a novel mechanistic approach, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. We conducted the first phase II, randomized, double-blind, placebo- and active-controlled trial, evaluating the analgesic efficacy, safety, and tolerability of cebranopadol in patients with moderate-to-severe chronic LBP with and without neuropathic pain component...
September 2017: Pain
https://www.readbyqxmd.com/read/28635181/buprenorphine-requires-concomitant-activation-of-nop-and-mop-receptors-to-reduce-cocaine-consumption
#16
Marsida Kallupi, Qianwei Shen, Giordano de Guglielmo, Dennis Yasuda, V Blair Journigan, Nurulain T Zaveri, Roberto Ciccocioppo
Buprenorphine's clinical use is approved for the treatment of heroin addiction; however, evidence supporting its efficacy in cocaine abuse also exists. While for heroin it has been demonstrated that the effect of buprenorphine is mediated by its ability to activate μ-opioid peptide receptor (MOP) receptors, the mechanism through which it attenuates cocaine intake remains elusive. We explored this mechanism using operant models where rodents were trained to chronically self-administer cocaine for 2 hours daily...
June 21, 2017: Addiction Biology
https://www.readbyqxmd.com/read/28623508/clinical-pharmacokinetic-characteristics-of-cebranopadol-a-novel-first-in-class-analgesic
#17
Elke Kleideiter, Chiara Piana, Shaonan Wang, Robert Nemeth, Michael Gautrois
BACKGROUND AND OBJECTIVES: Cebranopadol is a novel first-in-class analgesic acting as a nociceptin/orphanin FQ peptide and opioid peptide receptor agonist with central analgesic activity. It is currently in clinical development for the treatment of chronic pain conditions. This trial focuses on the clinical pharmacokinetic (PK) properties of cebranopadol after oral single- and multiple-dose administration. METHODS: The basic PK properties of cebranopadol were assessed by means of noncompartmental methods in six phase I clinical trials in healthy subjects and patients...
June 16, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28583844/nociceptin-orphanin-fq-antagonizes-lipopolysaccharide-stimulated-proliferation-migration-and-inflammatory-signaling-in-human-glioblastoma-u87-cells
#18
Andrea Bedini, Monica Baiula, Gabriele Vincelli, Francesco Formaggio, Sara Lombardi, Marco Caprini, Santi Spampinato
Glioblastoma is among the most aggressive brain tumors and has an exceedingly poor prognosis. Recently, the importance of the tumor microenvironment in glioblastoma cell growth and progression has been emphasized. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and endogenous ligands originating from dying cells or the extracellular matrix involved in host defense and in inflammation. G-protein coupled receptors (GPCRs) have gained interest in anti-tumor drug discovery due to the role that they directly or indirectly play by transactivating other receptors, causing cell migration and proliferation...
September 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28419415/allostery-at-opioid-receptors-modulation-with-small-molecule-ligands
#19
REVIEW
Kathryn E Livingston, John R Traynor
Opioid receptors are 7-transmembrane domain receptors that couple to heterotrimeric G proteins. The endogenous ligands for opioid receptors are peptides which bind to the orthosteric site on the receptors. The μ-opioid receptor is the target for opioid analgesics, while the δ-opioid receptor has been suggested as a target for pain management, migraine and depression. Similarly, κ-opioid receptors are involved in pain and depression and nociceptin receptors in pain and mood behaviours. However, exogenous orthosteric ligands for opioid receptors cause a myriad of on-target side effects...
April 18, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28383520/structure-and-conformation-activity-studies-of-nociceptin-orphanin-fq-receptor-dimeric-ligands
#20
Salvatore Pacifico, Alfonso Carotenuto, Diego Brancaccio, Ettore Novellino, Erika Marzola, Federica Ferrari, Maria Camilla Cerlesi, Claudio Trapella, Delia Preti, Severo Salvadori, Girolamo Calò, Remo Guerrini
The peptide nociceptin/orphanin FQ (N/OFQ) and the N/OFQ receptor (NOP) constitute a neuropeptidergic system that modulates various biological functions and is currently targeted for the generation of innovative drugs. In the present study dimeric NOP receptor ligands with spacers of different lengths were generated using both peptide and non-peptide pharmacophores. The novel compounds (12 peptide and 7 nonpeptide ligands) were pharmacologically investigated in a calcium mobilization assay and in the mouse vas deferens bioassay...
April 6, 2017: Scientific Reports
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