{"id":1449,"date":"2017-06-05T14:58:41","date_gmt":"2017-06-05T05:58:41","guid":{"rendered":"http:\/\/misterx95.myds.me\/?p=1449"},"modified":"2017-06-05T14:58:41","modified_gmt":"2017-06-05T05:58:41","slug":"2017-06-09","status":"publish","type":"post","link":"https:\/\/misterx95.myds.me\/wordpress\/?p=1449","title":{"rendered":"2017.06.09"},"content":{"rendered":"

Methylglyoxal<\/span> evokes<\/span> pain<\/span> by stimulating<\/span> TRPA1<\/span>.<\/h1>\n
Andersson DA<\/span><\/a>1<\/span><\/sup>, Gentry C<\/span><\/a>, Light E<\/span><\/a>, Vastani N<\/span><\/a>, Vallortigara J<\/span><\/a>, Bierhaus A<\/span><\/a>, Fleming T<\/span><\/a>, Bevan S<\/span><\/a>.<\/div>\n
\n

Abstract<\/h3>\n
\n

Diabetic neuropathy is a severe complication of long-standing diabetes and one of the major etiologies of neuropathic pain<\/span>. Diabetes is associated with an increased formation of reactive oxygen species and the electrophilic dicarbonyl compound methylglyoxal<\/span> (MG). Here we show that MG stimulates heterologously expressed TRPA1<\/span> in CHO cells and natively expressed TRPA1<\/span> in MDCK cells and DRG neurons. MG evokes<\/span> [Ca(2+)]i-responses in TRPA1<\/span> expressing DRG neurons but is without effect in neurons cultured from Trpa1<\/span>(-\/-) mice. Consistent with a direct, intracellular action, we show that methylglyoxal<\/span> is significantly more potent as a TRPA1<\/span> agonist when applied to the intracellular face of excised membrane patches than to intact cells. Local intraplantar administration of MG evokes<\/span> a pain<\/span> response in Trpa1<\/span>(+\/+) but not in Trpa1<\/span>(-\/-) mice. Furthermore, persistently increased MG levels achieved by two weeks pharmacological inhibition of glyoxalase-1 (GLO-1), the rate-limiting enzyme responsible for detoxification of MG, evokes<\/span> a progressive and marked thermal (cold and heat) and mechanical hypersensitivity in wildtype but not in Trpa1<\/span>(-\/-) mice. Our results thus demonstrate that TRPA1<\/span> is required both for the acute pain<\/span> response evoked by topical MG and for the long-lasting pronociceptive effects associated with elevated MG in vivo. In contrast to our observations in DRG neurons, MG evokes<\/span> indistinguishable [Ca(2+)]i-responses in pancreatic \u03b2-cells cultured from Trpa1<\/span>(+\/+) and Trpa1<\/span>(-\/-) mice. In vivo, the TRPA1<\/span> antagonist HC030031 impairs glucose clearance in the glucose tolerance test both in Trpa1<\/span>(+\/+) and Trpa1<\/span>(-\/-) mice, indicating a non-TRPA1<\/span> mediated effect and suggesting that results obtained with this compound should be interpreted with caution. Our results show that TRPA1<\/span> is the principal target for MG in sensory neurons but not in pancreatic \u03b2-cells and that activation of TRPA1<\/span> by MG produces a painful neuropathy with the behavioral hallmarks of diabetic neuropathy.<\/p>\n

journal.pone.0077986<\/a><\/p>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

Methylglyoxal evokes pain by stimulating TRPA1. Andersson DA1, Gentry C, Light E, Vastani N, Vallortigara J, Bierhaus A, Fleming T, Bevan S. Abstract Diabetic neuropathy is a severe complication of long-standing diabetes and one of the major etiologies of neuropathic pain. Diabetes is associated with an increased formation of reactive oxygen species and the electrophilic […]<\/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\/1449"}],"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=1449"}],"version-history":[{"count":1,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/1449\/revisions"}],"predecessor-version":[{"id":1451,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/1449\/revisions\/1451"}],"wp:attachment":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=1449"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=1449"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=1449"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}