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Kor Antagonist

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https://www.readbyqxmd.com/read/27891289/nor-bni-antagonism-of-kappa-opioid-agonist-induced-reinstatement-of-ethanol-seeking-behavior
#1
Erin Harshberger, Emily A Gilson, Kelli Gillett, Jasmine H Stone, Laila El Amrani, Glenn R Valdez
Recent work suggests that the dynorphin (DYN)/kappa opioid receptor (KOR) system may be a key mediator in the behavioral effects of alcohol. The objective of the present study was to examine the ability of the KOR antagonist norbinaltorphimine (nor-BNI) to attenuate relapse to ethanol seeking due to priming injections of the KOR agonist U50,488 at time points consistent with KOR selectivity. Male Wistar rats were trained to self-administer a 10% ethanol solution, and then responding was extinguished. Following extinction, rats were injected with U50,488 (0...
2016: Journal of Addiction
https://www.readbyqxmd.com/read/27849613/endogenous-central-amygdala-mu-opioid-receptor-signaling-promotes-sodium-appetite-in-mice
#2
Craig M Smith, Lesley L Walker, Tanawan Leeboonngam, Michael J McKinley, Derek A Denton, Andrew J Lawrence
Due to the importance of dietary sodium and its paucity within many inland environments, terrestrial animals have evolved an instinctive sodium appetite that is commensurate with sodium deficiency. Despite a well-established role for central opioid signaling in sodium appetite, the endogenous influence of specific opioid receptor subtypes within distinct brain regions remains to be elucidated. Using selective pharmacological antagonists of opioid receptor subtypes, we reveal that endogenous mu-opioid receptor (MOR) signaling strongly drives sodium appetite in sodium-depleted mice, whereas a role for kappa (KOR) and delta (DOR) opioid receptor signaling was not detected, at least in sodium-depleted mice...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27842940/nalmefene-for-the-management-of-alcohol-dependence-review-on-its-pharmacology-mechanism-of-action-and-meta-analysis-on-its-clinical-efficacy
#3
Karl Mann, Lars Torup, Per Sørensen, Antoni Gual, Robert Swift, Brendan Walker, Wim van den Brink
Nalmefene, a mu- and delta-opioid receptor (MOR, DOR) antagonist and a partial kappa-opioid receptor (KOR) agonist, is approved in the European Union and other countries for the reduction of alcohol consumption in alcohol dependent patients with a high drinking risk level according to WHO ("target population"). This review presents an overview of nalmefene׳s pharmacology, its mechanisms of action and a meta-analysis on its efficacy in reducing alcohol consumption. The review was based on a systematic search of the literature...
November 11, 2016: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27821345/n-18-f-fluoropropyljdtic-for-%C3%AE%C2%BA-opioid-receptor-pet-imaging-radiosynthesis-pre-clinical-evaluation-and-metabolic-investigation-in-comparison-with-parent-jdtic
#4
Sébastien Schmitt, Jérôme Delamare, Olivier Tirel, Fabien Fillesoye, Martine Dhilly, Cécile Perrio
INTRODUCTION: To image kappa opioid receptor (KOR) for preclinical studies, N-fluoropropylJDTic 9 derived from the best-established KOR antagonist JDTic, was labeled with fluorine-18. METHODS: Radiosynthesis of [(18)F]9 was achieved according to an automated two-step procedure from [(18)F]-fluoride. Peripheral and cerebral distributions were determined by ex vivo experiments and by PET imaging in mouse. Radiometabolism studies were performed both in vivo in mice and in vitro in mouse and human liver microsomes...
September 26, 2016: Nuclear Medicine and Biology
https://www.readbyqxmd.com/read/27818236/a-role-for-the-mu-opioid-receptor-in-the-antidepressant-effects-of-buprenorphine
#5
Shivon A Robinson, Rebecca L Erickson, Caroline A Browne, Irwin Lucki
Buprenorphine (BPN), a mixed opioid drug with high affinity for mu (MOR) and kappa (KOR) opioid receptors, has been shown to produce behavioral responses in rodents that are similar to those of antidepressant and anxiolytic drugs. Although recent studies have identified KORs as a primary mediator of BPN's effects in rodent models of depressive-like behavior, the role of MORs in BPN's behavioral effects has not been as well explored. The current studies investigated the role of MORs in mediating conditioned approach behavior in the novelty-induced hypophagia (NIH) test, a behavioral measure previously shown to be sensitive to chronic treatment with antidepressant drugs...
November 3, 2016: Behavioural Brain Research
https://www.readbyqxmd.com/read/27797517/structure-activity-relationships-of-des-arg-7-dynorphin-a-analogues-at-the-kappa-opioid-receptor
#6
Cyf N Ramos-Colon, Yeon Sun Lee, Michael Vincent Remesic, Sara M Hall, Justin LaVigne, Peg Davis, Alexander J Sandweiss, Mary I McIntosh, Jessica Hanson, Tally M Largent-Milnes, Todd W Vanderah, John M Streicher, Frank Porreca, Victor J Hruby
Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the kappa opioid receptor (KOR), and its structure-activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg(7) residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg(7)]-Dyn A analogues found that Arg(7) is not a key residue and even deletion of the residue does not affect biological activities at the KOR...
October 31, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27743931/modulation-of-serotonin-transporter-function-by-kappa-opioid-receptor-ligands
#7
Santhanalakshmi Sundaramurthy, Balasubramaniam Annamalai, Devadoss J Samuvel, Toni S Shippenberg, Lankupalle D Jayanthi, Sammanda Ramamoorthy
Kappa opioid receptor (KOR) agonists produce dysphoria and psychotomimesis. While KOR agonists produce pro-depressant-like effects, KOR antagonists produce anti-depressant-like effects in rodent models. The cellular mechanisms and downstream effector(s) by which KOR ligands produce these effects are not clear. KOR agonists modulate serotonin (5-HT) transmission in the brain regions implicated in mood and motivation regulation. Presynaptic serotonin transporter (SERT) activity is critical in the modulation of synaptic 5-HT and, subsequently, in mood disorders...
October 12, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27741398/a-fluorine-18-labeled-antagonist-for-pet-imaging-of-kappa-opioid-receptors
#8
Zhengxin Cai, Song Ye Li, Richard Pracitto, Antonio Navarro, Anupama Shirali, Jim Ropchan, Yiyun Henry Huang
Kappa opioid receptor (KOR) antagonists are potential drug candidates for diseases such as treatment-refractory depression, anxiety, and addictive disorders. PET imaging radiotracers for KOR can be used in occupancy study to facilitate drug development, and to investigate the roles of KOR in health and diseases. We have previously developed two 11C-labeled antagonist radiotracers with high affinity and selectivity toward KOR. What is limiting their wide applications is the short half-life of 11C. Herein, we report the synthesis of a first 18F-labeled KOR antagonist radiotracer and the initial PET imaging study in a non-human primate...
October 14, 2016: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/27736318/norbni-blocks-the-adverse-effects-of-morphine-following-spinal-cord-injury
#9
Miriam Aceves, Eric Bancroft, Alejandro R Aceves, Michelle Hook
Opioids are frequently used for the treatment of pain following spinal cord injury (SCI). Unfortunately, we have shown that morphine administered in the acute phase of SCI results in significant, adverse secondary consequences including compromised locomotor and sensory recovery. Similarly, we showed that selective activation of the κ-opioid receptor (KOR), even at a dose 32-fold lower than morphine, is sufficient to attenuate recovery of locomotor function. In the current study, we tested whether activation of the KOR is necessary to produce morphine's adverse effects using nor-Binaltorphimine (norBNI), a selective KOR antagonist...
October 13, 2016: Journal of Neurotrauma
https://www.readbyqxmd.com/read/27725218/opioid-subtype-and-cell-type-dependent-regulation-of-inhibitory-synaptic-transmission-in-the-rat-insular-cortex
#10
Eiko Yokota, Yuko Koyanagi, Kiyofumi Yamamoto, Yoshiyuki Oi, Noriaki Koshikawa, Masayuki Kobayashi
The insular cortex (IC) plays a principal role in the regulation of pain processing. Although opioidergic agonists depress cortical excitatory synaptic transmission, little is known about opioidergic roles in inhibitory synaptic transmission. In the IC, the opioid receptors differentially regulate the excitatory propagation: agonists of the mu (MOR), delta (DOR), and kappa (KOR) exhibit suppressive, facilitative, and little effects, respectively. Thus, we aimed to examine the effects of opioid receptor agonists on unitary inhibitory postsynaptic currents (uIPSCs) in the IC...
December 17, 2016: Neuroscience
https://www.readbyqxmd.com/read/27700049/pharmacodynamic-relationships-between-duration-of-action-of-jdtic-like-kappa-opioid-receptor-antagonists-and-their-brain-and-plasma-pharmacokinetics-in-rats
#11
S Michael Owens, Gerald T Pollard, James L Howard, Timothy R Fennell, Rodney W Snyder, F Ivy Carroll
JDTic is a potent and selective κ-opioid receptor (KOR) antagonist that reverses U50,488-induced diuresis in rats. It partitions into brain with a duration of action lasting for weeks. In a search for KOR antagonists that do not accumulate in the brain, we compared single doses of five methylated JDTic analogs (RTI-97, -194, -212, -240, and -241) for reversal of U50,488 diuresis and pharmacokinetic (PK) properties. All six compounds showed potent and selective KOR antagonism in a [(35)S]GTPγS binding assay...
October 4, 2016: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/27699938/kappa-opioid-antagonists-for-psychiatric-disorders-from-bench-to-clinical-trials
#12
William A Carlezon, Andrew D Krystal
Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry...
October 2016: Depression and Anxiety
https://www.readbyqxmd.com/read/27688945/kappa-opioid-receptors-differentially-regulate-low-and-high-levels-of-ethanol-intake-in-female-mice
#13
Ashlee Van't Veer, Karen L Smith, Bruce M Cohen, William A Carlezon, Anita J Bechtholt
INTRODUCTION: Studies in laboratory animals and humans indicate that endogenous opioids play an important role in regulating the rewarding value of various drugs, including ethanol (EtOH). Indeed, opioid antagonists are currently a front-line treatment for alcoholism in humans. Although roles for mu- and delta-opioid receptors have been characterized, the contribution of kappa-opioid receptors (KORs) is less clear. There is evidence that changes in KOR system function can decrease or increase EtOH drinking, depending on test conditions...
September 2016: Brain and Behavior
https://www.readbyqxmd.com/read/27648372/pet-imaging-reveals-sex-differences-in-kappa-opioid-receptor-availability-in-humans-in-vivo
#14
Aishwarya Vijay, Shuo Wang, Patrick Worhunsky, Ming-Qiang Zheng, Nabeel Nabulsi, Jim Ropchan, Suchitra Krishnan-Sarin, Yiyun Huang, Evan D Morris
Opioid receptors may play critical roles in alcoholism and other addictions, addiction withdrawal, and depression and are considered pharmacological targets for treatment of these conditions. Sex differences have been demonstrated in mu (MOR) and delta (DOR) opioid receptors in humans, in vivo. In addition, sex differences have been observed in efficacy of treatment targeting kappa opioid receptors (KOR). Our goal in the present study was to compare the availability of KOR (1) between healthy control (HC) men and women...
2016: American Journal of Nuclear Medicine and Molecular Imaging
https://www.readbyqxmd.com/read/27634008/chronic-kappa-opioid-receptor-activation-modulates-nr2b-implication-in-treatment-resistant-depression
#15
Shalini Dogra, Ajeet Kumar, Deepmala Umrao, Amogh A Sahasrabuddhe, Prem N Yadav
Psychotomimetic and prodepressive effect by kappa opioid receptor (KOR) activation in rodents and human is widely known. Significantly, recent clinical investigations demonstrated the salutary effects of KOR antagonists in patients with treatment resistant depression, indicating essential role of KOR signaling in refractory depression. This study was undertaken to reveal the molecular determinant of KOR mediated depression and antidepressant response of KOR antagonist. We observed that chronic KOR activation by U50488, a selective KOR agonist, significantly increased depression like symptoms (behavioral despair, anhedonia and sociability) in C57BL/6J mice, which were blocked by KOR antagonist norBNI and antidepressant imipramine, but not by fluoxetine or citalopram...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27624520/an-lp1-analogue-selective-mor-agonist-with-a-peculiar-pharmacological-profile-used-to-scrutiny-the-ligand-binding-domain
#16
Simone Ronsisvalle, Giuseppina Aricò, Federica Panarello, Angelo Spadaro, Lorella Pasquinucci, Maria S Pappalardo, Carmela Parenti, Nicole Ronsisvalle
The hypothesis that central analgesia with reduced side effects is obtainable by occupying an 'allosteric' site in the MOR ligand binding domain requires the development of new ligands with peculiar pharmacological profile to be used as tools. New benzomorphan derivatives, analogues of LP1, a multitarget MOR agonist/DOR antagonist, were designed to examine in depth MOR ligand binding domain. Compound 5, bearing a diphenylic N-substituent on the benzomorphan nucleus, showed an affinity (Ki(μ)=0.5±0.2nM) comparable to that of LP1 and a better selectivity versus DOR and KOR...
November 1, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27605628/long-term-reduction-of-kappa-opioid-receptor-function-by-the-biased-ligand-norbinaltorphimine-requires-c-jun-n-terminal-kinase-activity-and-new-protein-synthesis-in-peripheral-sensory-neurons
#17
Raehannah J Jamshidi, Laura C Sullivan, Blaine A Jacobs, Teresa A Chavera, Kelly A Berg, William P Clarke
A single administration of the κ opioid receptor (KOR) antagonist, norbinaltorphimine (norBNI), produces long-term reduction in KOR function in heterologous expression systems and brain that is mediated by activation of c-Jun N-terminal kinase (JNK). In this study, we examined the long-term effects of norBNI on adult rat peripheral sensory neurons in vivo and ex vivo. Following a single intraplantar (i.pl.) injection of norBNI into the hind paw, peripheral KOR-mediated antinociception in the ipsilateral, but not the contralateral, hindpaw was abolished for at least 9 days...
November 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27530869/ignavine-a-novel-allosteric-modulator-of-the-%C3%AE-opioid-receptor
#18
Katsuya Ohbuchi, Chika Miyagi, Yasuyuki Suzuki, Yasuharu Mizuhara, Keita Mizuno, Yuji Omiya, Masahiro Yamamoto, Eiji Warabi, Yuka Sudo, Akinobu Yokoyama, Kanako Miyano, Takatsugu Hirokawa, Yasuhito Uezono
Processed Aconiti tuber (PAT) is used to treat pain associated with various disorders. Although it has been demonstrated that the κ opioid receptor (KOR) signaling pathway is a mediator of the analgesic effect of PAT, active components affecting opioid signaling have not yet been identified. In this study, we explored candidate components of PAT by pharmacokinetic analysis and identified ignavine, which is a different structure from aconitine alkaloids. A receptor binding assay of opioid receptors showed that ignavine specifically binds the μ opioid receptor (MOR), not the KOR...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27466337/identification-of-the-kappa-opioid-receptor-as-a-therapeutic-target-for-oligodendrocyte-remyelination
#19
Feng Mei, Sonia R Mayoral, Hiroko Nobuta, Fei Wang, Caroline Desponts, Daniel S Lorrain, Lan Xiao, Ari J Green, David Rowitch, Jennifer Whistler, Jonah R Chan
UNLABELLED: Remyelinating therapies seek to promote restoration of function and normal cellular architecture following demyelination in diseases, such as multiple sclerosis (MS). Functional screening for small molecules or novel targets for remyelination is a major hurdle to the identification and development of rational therapeutics for MS. Recent findings and technical advances provide us with a unique opportunity to provide insight into the cell autonomous mechanisms for remyelination and address this unmet need...
July 27, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27378583/the-contribution-of-activated-peripheral-kappa-opioid-receptors-kors-in-the-inflamed-knee-joint-to-anti-nociception
#20
Sun Wook Moon, Eui Ho Park, Hye Rim Suh, Duk Hwan Ko, Yang In Kim, Hee Chul Han
The systemic administration of opioids can be used for their strong analgesic effect. However, extensive activation of opioid receptors (ORs) beyond the targeted tissue can cause dysphoria, pruritus, and constipation. Therefore, selective activation of peripheral ORs present in the afferent fibers of the targeted tissue can be considered a superior strategy in opioid analgesia to avoid potential adverse effects. The purpose of this study was to clarify the role of peripheral kappa opioid receptors (kORs) in arthritic pain for the possible use of peripheral ORs as a target in anti-nociceptive therapy...
October 1, 2016: Brain Research
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