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  1. Article ; Online: The kappa opioid receptor agonist U50,488H did not affect brain-stimulation reward while it elicited conditioned place aversion in mice

    Peng Huang / Taylor A. Gentile / John W. Muschamp / Lee-Yuan Liu-Chen

    BMC Research Notes, Vol 13, Iss 1, Pp 1-

    2020  Volume 6

    Abstract: Abstract Objective Selective kappa opioid receptor (KOR) agonists were shown to produce a dose-dependent depression of brain-stimulation reward (BSR) in the rat intracranial self-stimulation (ICSS) tests. However, limited studies using mice produced less ...

    Abstract Abstract Objective Selective kappa opioid receptor (KOR) agonists were shown to produce a dose-dependent depression of brain-stimulation reward (BSR) in the rat intracranial self-stimulation (ICSS) tests. However, limited studies using mice produced less conclusive results. Here the effects of U50,488H were re-examined on BSR in mice with a larger cohort of animals. Results Forty C57BL/6J male mice were implanted with the electrodes in medial forebrain bundle. About a week after surgery, mice were subject to ICSS training. Only eighteen passed the two-phase procedures, at which point they readily spun the wheels to obtain reinforcing effect of BSR, and were used for the ICSS tests. Compared with saline (s.c.), U50,488H (2 mg/kg, s.c.) did not have effects on the BSR thresholds within 1 h post-treatment, while it decreased the maximum wheel-spinning rates in a time-dependent manner. In contrast, cocaine (5 mg/kg, s.c.) decreased the BSR thresholds time-dependently without affecting the maximum wheel-spinning rates in the same cohort of mice, demonstrating the validity of our mouse ICSS models. For comparison, U50,488H (2 mg/kg, s.c.) induced significant conditioned place aversion (CPA) in a different cohort of mice without surgeries. Thus, ICSS may not be an appropriate test for KOR agonist-induced aversion in mice.
    Keywords Kappa opioid receptor ; U50,488H ; Brain-stimulation reward ; ICSS ; Conditioned place aversion ; Medicine ; R ; Biology (General) ; QH301-705.5 ; Science (General) ; Q1-390
    Subject code 616
    Language English
    Publishing date 2020-08-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: A novel Oprm1-Cre mouse maintains endogenous expression, function and enables detailed molecular characterization of μ-opioid receptor cells.

    Juliet Mengaziol / Amelia D Dunn / Gregory Salimando / Lisa Wooldridge / Jordi Crues-Muncunill / Darrell Eacret / Chongguang Chen / Kathryn Bland / Lee-Yuan Liu-Chen / Michelle E Ehrlich / Gregory Corder / Julie A Blendy

    PLoS ONE, Vol 17, Iss 12, p e

    2022  Volume 0270317

    Abstract: Key targets of both the therapeutic and abused properties of opioids are μ-opioid receptors (MORs). Despite years of research investigating the biochemistry and signal transduction pathways associated with MOR activation, we do not fully understand the ... ...

    Abstract Key targets of both the therapeutic and abused properties of opioids are μ-opioid receptors (MORs). Despite years of research investigating the biochemistry and signal transduction pathways associated with MOR activation, we do not fully understand the cellular mechanisms underlying opioid addiction. Given that addictive opioids such as morphine, oxycodone, heroin, and fentanyl all activate MORs, and current therapies such as naloxone and buprenorphine block this activation, the availability of tools to mechanistically investigate opioid-mediated cellular and behavioral phenotypes are necessary. Therefore, we derived, validated, and applied a novel MOR-specific Cre mouse line, inserting a T2A cleavable peptide sequence and the Cre coding sequence into the MOR 3'UTR. Importantly, this line shows specificity and fidelity of MOR expression throughout the brain and with respect to function, there were no differences in behavioral responses to morphine when compared to wild type mice, nor are there any alterations in Oprm1 gene expression or receptor density. To assess Cre recombinase activity, MOR-Cre mice were crossed with the floxed GFP-reporters, RosaLSLSun1-sfGFP or RosaLSL-GFP-L10a. The latter allowed for cell type specific RNA sequencing via TRAP (Translating Ribosome Affinity Purification) of striatal MOR+ neurons following opioid withdrawal. The breadth of utility of this new tool will greatly facilitate the study of opioid biology under varying conditions.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Studies toward bivalent κ opioids derived from salvinorin A

    Thomas A. Munro / Wei Xu / Douglas M. Ho / Lee-Yuan Liu-Chen / Bruce M. Cohen

    Beilstein Journal of Organic Chemistry, Vol 9, Iss 1, Pp 2916-

    heteromethylation of the furan ring reduces affinity

    2013  Volume 2924

    Abstract: The recent crystal structure of the κ-opioid receptor (κ-OR) revealed, unexpectedly, that the antagonist JDTic is a bivalent ligand: in addition to the orthosteric pocket occupied by morphinans, JDTic also occupies a distinct (allotopic) pocket. ... ...

    Abstract The recent crystal structure of the κ-opioid receptor (κ-OR) revealed, unexpectedly, that the antagonist JDTic is a bivalent ligand: in addition to the orthosteric pocket occupied by morphinans, JDTic also occupies a distinct (allotopic) pocket. Mutagenesis data suggest that salvinorin A (1) also binds to this allotopic pocket, adjacent to the aspartate residue that anchors the basic nitrogen atom of classical opiates (Asp138). It has been suggested that an H-bond donor appended to 1 might interact with Asp138, increasing affinity. Such a bivalent ligand might also possess altered functional selectivity. Based on modeling and known N-furanylmethyl opioid antagonists, we appended H-bond donors to the furan ring of 1. (Dimethylamino)methyl groups at C-15 or C-16 abolished affinity for κ-OR. Hydroxymethylation at C-16 was tolerated, but 15,16-bis-hydroxymethylation was not. Since allosteric modulators may go undetected in binding assays, we also tested these and other low-affinity derivatives of 1 for allosteric modulation of dynorphin A in the [35S]GTPγS assay. No modulation was detected. As an alternative attachment point for bivalent derivatives, we prepared the 2-(hydroxyethoxy)methyl ether, which retained high affinity for κ-OR. We discuss alternative design strategies for linked, fused or merged bivalent derivatives of 1.
    Keywords allotopic ; bivalent ligand ; designed multiple ligand ; JDTic ; κ-opioid receptor ; natural products ; Salvinorin A ; Science ; Q ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2013-12-01T00:00:00Z
    Publisher Beilstein-Institut
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Isoquinoline Alkaloids Isolated from Corydalis yanhusuo and Their Binding Affinities at the Dopamine D1 Receptor

    David Y. W. Lee / Lee-Yuan Liu-Chen / Bryan L. Roth / Niels H. Jensen / Wei Xu / Zhong-Ze Ma

    Molecules, Vol 13, Iss 9, Pp 2303-

    2008  Volume 2312

    Abstract: Bioactivity-guided fractionation of Corydalis yanhusuo has resulted in the isolation of eight known isoquinoline alkaloids - tetrahydropalmatine, isocorypalmine, stylopine, corydaline, columbamine, coptisin, 13-methylpalmatine, and dehydrocorybulbine. ... ...

    Abstract Bioactivity-guided fractionation of Corydalis yanhusuo has resulted in the isolation of eight known isoquinoline alkaloids - tetrahydropalmatine, isocorypalmine, stylopine, corydaline, columbamine, coptisin, 13-methylpalmatine, and dehydrocorybulbine. The tertiary alkaloids were further analyzed by chiral HPLC to determine the ratios of d-and l-isomers. The isolated compounds were screened for their binding affinities at the dopamine D1 receptor. Isocorypalmine had the highest affinity (Ki = 83 nM). The structure-affinity relationships of these alkaloids are discussed.
    Keywords Corydalis yanhusuo ; Isoquinoline alkaloids ; d/l Ratio ; Chiral HPLC ; Dopamine receptor ; Organic chemistry ; QD241-441
    Language English
    Publishing date 2008-09-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: 8-epi-Salvinorin B

    Thomas A. Munro / Katharine K. Duncan / Richard J. Staples / Wei Xu / Lee-Yuan Liu-Chen / Cécile Béguin / William A. Carlezon Jr. / Bruce M. Cohen

    Beilstein Journal of Organic Chemistry, Vol 3, Iss 1, p

    crystal structure and affinity at the κ opioid receptor

    2007  Volume 1

    Abstract: There have been many reports of epimerization of salvinorins at C-8 under basic conditions, but little evidence has been presented to establish the structure of these compounds. We report here the first crystal structure of an 8-epi-salvinorin or ... ...

    Abstract There have been many reports of epimerization of salvinorins at C-8 under basic conditions, but little evidence has been presented to establish the structure of these compounds. We report here the first crystal structure of an 8-epi-salvinorin or derivative: the title compound, 2b. The lactone adopts a boat conformation with the furan equatorial. Several lines of evidence suggest that epimerization proceeds via enolization of the lactone rather than a previously proposed indirect mechanism. Consistent with the general trend in related compounds, the title compound showed lower affinity at the kappa opioid receptor than the natural epimer salvinorin B (2a). The related 8-epi-acid 4b showed no affinity.
    Keywords Science ; Q ; Organic chemistry ; QD241-441
    Language English
    Publishing date 2007-01-01T00:00:00Z
    Publisher Beilstein-Institut
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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