{"id":1524,"date":"2017-10-13T10:42:19","date_gmt":"2017-10-13T01:42:19","guid":{"rendered":"http:\/\/misterx95.myds.me\/?p=1524"},"modified":"2017-10-13T10:42:19","modified_gmt":"2017-10-13T01:42:19","slug":"journal-club-2017-10-13","status":"publish","type":"post","link":"https:\/\/misterx95.myds.me\/wordpress\/?p=1524","title":{"rendered":"Journal Club 2017. 10. 13."},"content":{"rendered":"<p><a href=\"http:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2017\/10\/synergistic-antipruritic-effects-of-gamma-aminobutyric-acid-A-and-B-agonists-ina-a-mouse-model-of-atopic-dermatitis.pdf\">synergistic antipruritic effects of gamma aminobutyric acid A and B agonists ina a mouse model of atopic dermatitis<\/a><\/p>\n<p>Ferda Cevikbas, PhD,a,b* Joao M. Braz, PhD,a* Xidao Wang, PhD,a Carlos Solorzano, PhD,a Mathias Sulk, MD,b,c<br \/>\nTimo Buhl, MD,b,d Martin Steinhoff, PhD,b,e,f,g,h and Allan I. Basbaum, PhDa<\/p>\n<p>&nbsp;<\/p>\n<p>Atopic dermatitis (AD), an inflammatory, relapsing chronic<br \/>\npruritic skin disease, is an often intractable form of chronic itch<br \/>\nthat negatively impacts the quality of life of millions of patients.1<br \/>\nUnfortunately, because chronic itch conditions have very<br \/>\ndifferent etiologies, most treatments have poor outcomes and<br \/>\nare accompanied by unacceptable adverse side effects, notably<br \/>\nsedation.2 Clearly, a better understanding of the pathophysiology<br \/>\nof these chronic itch conditions is critical to designing successful<br \/>\ntherapeutic strategies.<br \/>\nStudies of the etiology of chronic itch3 generally focus on<br \/>\nchanges in skin and immune dysfunction. However, there is<br \/>\nnow considerable evidence for a contribution of primary afferent<br \/>\npruritoceptors that transmit itch messages to spinal cord and<br \/>\nbrainstem circuits engaged by and that regulate these messages.4<br \/>\nOf particular interest are studies demonstrating commonalities in<br \/>\nthe mechanisms underlying nerve injury-induced neuropathic<br \/>\npain and itch and the possibility that comparable approaches<br \/>\nmay be appropriate for their management.5<br \/>\nAlthough there is evidence for specificity in the transmission of<br \/>\nitch and pain messages at the level of the primary afferent<br \/>\nnociceptor and pruritoceptor,6,7 both pain and itch are under<br \/>\nspinal cord inhibitory interneuron-mediated control. For example,<br \/>\nloss of spinal cord gamma aminobutyric acid (GABA) or glycinergic<br \/>\nfunction is a major contributor to the spontaneous pain and hypersensitivity<br \/>\nthat develops following nerve injury.8-10 Moreover,<br \/>\npersistent scratching, a manifestation of chronic itch, occurs in the<br \/>\nBhlhb5 mutant mouse, in which there is dramatic loss of dorsal<br \/>\nhorn GABAergic inhibitory interneurons.11 Ablation of glycinergic<br \/>\ninterneurons also induces excessive scratching and pain.12<br \/>\nAnd in a model of dry skin\u2013induced scratching in the mouse,<br \/>\nGABA and glycine receptor antagonists can block scratchinginduced<br \/>\ninhibition of firing in superficial dorsal horn neurons.13<br \/>\nFinally, in patients, acute withdrawal of intrathecal baclofen, a<br \/>\nGABA-B receptor agonist, can induce pruritus.14<br \/>\nGiven the evidence for a potential contribution of GABA<br \/>\nagonists in the management of pruritus, it is surprising that there<br \/>\nare no studies that assessed their utility in preclinical or clinical<br \/>\nconditions. Here, we demonstrate that both GABA-A and<\/p>\n<p>GABA-B agonists are not only effective in models of acute itch,<br \/>\nbut we also show that systemic administration of very low doses<br \/>\nof these agonists has synergistic antipruritic effects in IL-31<br \/>\noverexpressing transgenic mouse, a model of AD15 that is refractory<br \/>\nto antihistamines1,16 and thus particularly difficult to<br \/>\nmanage. Most importantly, the antipruritic synergy could be produced<br \/>\nwithout concomitant sedation. Finally, we show that sustaining<br \/>\nhigh levels of GABA inhibition can be achieved using<br \/>\nintraspinal transplantation of cortical GABAergic interneuron<br \/>\nprecursor cells. The transplants not only attenuated spontaneous<br \/>\nscratching but also dramatically reduced skin lesions in the IL-<br \/>\n31 overexpressing transgenic mouse (IL-31Tg) mice.<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>synergistic antipruritic effects of gamma aminobutyric acid A and B agonists ina a mouse model of atopic dermatitis Ferda Cevikbas, PhD,a,b* Joao M. Braz, PhD,a* Xidao Wang, PhD,a Carlos Solorzano, PhD,a Mathias Sulk, MD,b,c Timo Buhl, MD,b,d Martin Steinhoff, PhD,b,e,f,g,h and Allan I. Basbaum, PhDa &nbsp; Atopic dermatitis (AD), an inflammatory, relapsing chronic pruritic skin [&hellip;]<\/p>\n","protected":false},"author":8,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}}},"categories":[1],"tags":[],"_links":{"self":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/1524"}],"collection":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/users\/8"}],"replies":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=1524"}],"version-history":[{"count":1,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/1524\/revisions"}],"predecessor-version":[{"id":1526,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/1524\/revisions\/1526"}],"wp:attachment":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=1524"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=1524"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=1524"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}