Facilitation of MrgprD by TRP-A1 promotes neuropathic pain<\/a><\/p>\nChangming Wang,*,\u2020,\u2021,\u00a7 Leying Gu,*,\u2020,\u2021,\u00a7 Yonglan Ruan,*,\u2020,\u2021,\u00a7 Xiao Geng,*,\u2020,\u2021,\u00a7 Miao Xu,{ Niuniu Yang,*,k Lei Yu,*,\u2020 Yucui Jiang,*,\u2020 Chan Zhu,*,\u2020,\u2021,\u00a7 Yan Yang,*,\u2020,\u2021,\u00a7
\nYuan Zhou,*,\u2020,\u2021,\u00a7 Xiaowei Guan,*,\u2020,\u2021,\u00a7 Wenqin Luo,# Qin Liu,**,\u2020\u2020,\u2021\u2021 Xinzhong Dong,\u00a7\u00a7,{{ Guang Yu,*,\u2020,\u2021,\u00a7,1 Lei Lan,{,2 and Zongxiang Tang*,\u2020,\u2021,\u00a7
\n*School of Medicine and Life Sciences, \u2020Key Laboratory of Chinese Medicine for Prevention and Treatment of Neurological Diseases, \u2021State Key Laboratory Cultivation Base for Traditional Chinese Medicine Quality and Efficacy, and \u00a7Key Laboratory of Drug Target and Drug for Degenerative Disease of Jiangsu Province, Nanjing University of Chinese Medicine, Nanjing, China; {Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China; kDepartment of Traditional Chinese and Western Medicine, Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, China; #Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; **Department of Anesthesiology, \u2020\u2020Center for the Study of Itch, and \u2021\u2021Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA; and \u00a7\u00a7The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, and {{Howard Hughes Medical Institute, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
\nABSTRACT: Neuropathic pain remains a therapeutic challenge because of its complicated mechanisms. Mas-related GPCR D (MrgprD) is specifically expressed in small-diameter, nociceptive neurons of dorsal root ganglia (DRGs) and is implicated in pain modulation. However, the underlying mechanism of MrgprD involved in neuropathic pain remains elusive. In this study, we used behavioral experiments and physiologic examination methods to investigate the role of MrgprD in chronic constriction injury (CCI)\u2013induced neuropathic pain. We found that MrgprD is necessary for the initiation of mechanical hypersensitivity and cold allodynia, but not for heat allodynia. Moreover, we demonstrated that transient receptor potential cation channel (TRP)-A1 was the ion channel down- stream of MrgprD, and the b-alanine\u2013induced calcium signal was attributed mostly to TRP-A1 function. We further showed that PKA serves as a downstream mediator of b-alanine\u2013activated MrgprD signaling to activate TRP-A1 in DRG neurons and in human embryonic kidney 293 cells, to coexpress MrgprD and TRP-A1 plasmids. Finally, we found that the b-alanine\u2013induced pain behavior was increased, whereas the itching behavior was unchanged in CCI models compared with sham-injured animals. Knockout of TRPA1 also attenuated the b-alanine\u2013induced pain behavior in CCI models. In conclusion, MrgprD is essential in cold allodynia in CCI-induced neuropathic pain through the PKA\u2013TRP-A1 pathway. TRP-A1 facilitates MrgprD to development of neuropathic pain. Our findings reveal a novel mechanism of neuropathic pain formation and highlight MrgprD as a promising drug target for the treatment of neuropathic pain.\u2014Wang, C., Gu, L., Ruan, Y., Geng, X., Xu, M., Yang, N., Yu, L., Jiang, Y., Zhu, C., Yang, Y., Zhou, Y., Guan, X., Luo, W., Liu, Q., Dong, X., Yu, G., Lan, L., Tang, Z. Facilitation of MrgprD by TRP-A1 promotes neuropathic pain. FASEB J. 33, 1360\u20131373 (2019). www.fasebj.org
\nKEY WORDS: MrgprA1 \u2022 dorsal root ganglia (DRG) \u2022 protein kinase A (PKA)<\/p>\n","protected":false},"excerpt":{"rendered":"
Facilitation of MrgprD by TRP-A1 promotes neuropathic pain Facilitation of MrgprD by TRP-A1 promotes neuropathic pain Changming Wang,*,\u2020,\u2021,\u00a7 Leying Gu,*,\u2020,\u2021,\u00a7 Yonglan Ruan,*,\u2020,\u2021,\u00a7 Xiao Geng,*,\u2020,\u2021,\u00a7 Miao Xu,{ Niuniu Yang,*,k Lei Yu,*,\u2020 Yucui Jiang,*,\u2020 Chan Zhu,*,\u2020,\u2021,\u00a7 Yan Yang,*,\u2020,\u2021,\u00a7 Yuan Zhou,*,\u2020,\u2021,\u00a7 Xiaowei Guan,*,\u2020,\u2021,\u00a7 Wenqin Luo,# Qin Liu,**,\u2020\u2020,\u2021\u2021 Xinzhong Dong,\u00a7\u00a7,{{ Guang Yu,*,\u2020,\u2021,\u00a7,1 Lei Lan,{,2 and Zongxiang Tang*,\u2020,\u2021,\u00a7 *School of […]<\/p>\n","protected":false},"author":2,"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\/1703"}],"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\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=1703"}],"version-history":[{"count":1,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/1703\/revisions"}],"predecessor-version":[{"id":1705,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/1703\/revisions\/1705"}],"wp:attachment":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=1703"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=1703"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=1703"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}