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dc.creatorVasović, Dina
dc.creatorDivović, Branka
dc.creatorTreven, Marco
dc.creatorKnutson, Daniel
dc.creatorSteudle, Friederike
dc.creatorScholze, Petra
dc.creatorObradović, Aleksandar
dc.creatorFabjan, Jure
dc.creatorBrković, Božidar
dc.creatorSieghart, Werner
dc.creatorErnst, Margot
dc.creatorCook, James
dc.creatorSavić, Miroslav
dc.date.accessioned2020-07-02T13:21:42Z
dc.date.available2020-07-02T13:21:42Z
dc.date.issued2019
dc.identifier.issn1090-3801
dc.identifier.urihttps://smile.stomf.bg.ac.rs/handle/123456789/2384
dc.description.abstractgamma-Aminobutyric acid type A (GABA(A)) receptors containing the alpha 6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 mu M enhanced gamma-aminobutyric acid (GABA) currents at recombinant rat alpha 6 beta 3 gamma 2, alpha 6 beta 3 delta and alpha 6 beta 3 receptors, whereas it was inactive at most GABA(A) receptor subtypes containing other alpha subunits. DK-I-87-1 at concentrations below 1 mu M was inactive at alpha 6-containing receptors and only weakly modulated other GABA(A) receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 and 13 hr, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-hr period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy were already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. Significance Neuropathic pain induced by trigeminal nerve damage is poorly controlled by current treatments. DK-I-56-1 that positively modulates alpha 6 GABA(A) receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain.en
dc.publisherWiley, Hoboken
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/175076/RS//
dc.relationFWFAustrian Science Fund (FWF) [I2306]
dc.relationNational Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [MH096463, NS076517]
dc.relationMilwaukee Institute for Drug Discovery
dc.relationUniversity of Wisconsin-Milwaukee's Shimadzu Laboratory for Advanced and Applied Analytical Chemistry
dc.rightsopenAccess
dc.sourceEuropean Journal of Pain
dc.titleTrigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptorsen
dc.typearticle
dc.rights.licenseARR
dcterms.abstractДивовић, Бранка; Тревен, Марцо; Кнутсон, Даниел; Стеудле, Фриедерике; Брковић, Божидар; Сиегхарт, Wернер; Цоок, Јамес; Савић, Мирослав; Фабјан, Јуре; Ернст, Маргот; Васовић, Дина; Сцхолзе, Петра; Обрадовић, Aлександар;
dc.citation.volume23
dc.citation.issue5
dc.citation.spage973
dc.citation.epage984
dc.citation.other23(5): 973-984
dc.citation.rankM21
dc.identifier.wos000466443500013
dc.identifier.doi10.1002/ejp.1365
dc.identifier.pmid30633839
dc.identifier.scopus2-s2.0-85061056415
dc.identifier.fulltexthttps://smile.stomf.bg.ac.rs/bitstream/id/3430/2379.pdf
dc.type.versionpublishedVersion


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