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      Generation of aKOR-Creknockin mouse strain to study cells involved in kappa opioid signaling : generationofakor-creknockinmousestrain

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          Abstract

          <p class="first" id="P1">The kappa opioid receptor (KOR) has numerous important roles in the nervous system including the modulation of mood, reward, pain, and itch. In addition, KOR is expressed in many non-neuronal tissues. However, the specific cell types that express KOR are poorly characterized. Here, we report the development of a <i>KOR-Cre</i> knockin allele, which provides genetic access to cells that express KOR. In this mouse, <i>Cre recombinase</i> ( <i>Cre</i>) replaces the initial coding sequence of the <i>Opkr1</i> gene (encoding the kappa opioid receptor). We demonstrate that the <i>KOR-Cre</i> allele mediates recombination by embryonic day 14.5 (E14.5). Within the brain, <i>KOR-Cre</i> shows expression in numerous areas including the cerebral cortex, nucleus accumbens and striatum. In addition, this allele is expressed in epithelium and throughout many regions of the body including the heart, lung, and liver. Finally, we reveal that <i>KOR-Cre</i> mediates recombination of a subset of bipolar and amacrine cells in the retina. Thus, the <i>KOR-Cre</i> mouse line is a valuable new tool for conditional gene manipulation to enable the study of KOR. </p>

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          Most cited references 33

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          A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex.

          A key obstacle to understanding neural circuits in the cerebral cortex is that of unraveling the diversity of GABAergic interneurons. This diversity poses general questions for neural circuit analysis: how are these interneuron cell types generated and assembled into stereotyped local circuits and how do they differentially contribute to circuit operations that underlie cortical functions ranging from perception to cognition? Using genetic engineering in mice, we have generated and characterized approximately 20 Cre and inducible CreER knockin driver lines that reliably target major classes and lineages of GABAergic neurons. More select populations are captured by intersection of Cre and Flp drivers. Genetic targeting allows reliable identification, monitoring, and manipulation of cortical GABAergic neurons, thereby enabling a systematic and comprehensive analysis from cell fate specification, migration, and connectivity, to their functions in network dynamics and behavior. As such, this approach will accelerate the study of GABAergic circuits throughout the mammalian brain. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Targeted mutation of the DNA methyltransferase gene results in embryonic lethality

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              Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist.

              Salvia divinorum, whose main active ingredient is the neoclerodane diterpene Salvinorin A, is a hallucinogenic plant in the mint family that has been used in traditional spiritual practices for its psychoactive properties by the Mazatecs of Oaxaca, Mexico. More recently, S. divinorum extracts and Salvinorin A have become more widely used in the U.S. as legal hallucinogens. We discovered that Salvinorin A potently and selectively inhibited (3)H-bremazocine binding to cloned kappa opioid receptors. Salvinorin A had no significant activity against a battery of 50 receptors, transporters, and ion channels and showed a distinctive profile compared with the prototypic hallucinogen lysergic acid diethylamide. Functional studies demonstrated that Salvinorin A is a potent kappa opioid agonist at cloned kappa opioid receptors expressed in human embryonic kidney-293 cells and at native kappa opioid receptors expressed in guinea pig brain. Importantly, Salvinorin A had no actions at the 5-HT(2A) serotonin receptor, the principal molecular target responsible for the actions of classical hallucinogens. Salvinorin A thus represents, to our knowledge, the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A is a psychotomimetic selective for kappa opioid receptors, kappa opioid-selective antagonists may represent novel psychotherapeutic compounds for diseases manifested by perceptual distortions (e.g., schizophrenia, dementia, and bipolar disorders). Additionally, these results suggest that kappa opioid receptors play a prominent role in the modulation of human perception.
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                Author and article information

                Journal
                genesis
                genesis
                Wiley
                1526954X
                January 2016
                January 2016
                December 18 2015
                : 54
                : 1
                : 29-37
                Affiliations
                [1 ]Department of Neurobiology and the Pittsburgh Center for Pain Research; University of Pittsburgh; Pittsburgh Pennsylvania
                [2 ]Tsinghua University School of Medicine; Beijing China
                [3 ]Department of Biological Sciences and Center for the Neural Basis of Cognition; Carnegie Mellon University; Pittsburgh Pennsylvania
                [4 ]Departments of Anesthesiology and Pharmacology & Chemical Biology; University of Pittsburgh; Pittsburgh Pennsylvania
                Article
                10.1002/dvg.22910
                4747253
                26575788
                © 2015
                Product
                Self URI (article page): http://doi.wiley.com/10.1002/dvg.22910

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