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According to recent studies, nerve injury induces changes in glutamatergic transmission in the spinal cord and several supraspinal regions, including the periaqueductal gray (PAG). Among glutamate signaling components, accumulating evidence suggests that the glial glutamate transporter GLT1 plays a critical role in neuropathic pain. Indeed, GLT1 expression is reduced in the spinal cord but increased in the PAG after nerve injury, suggesting that the role of GLT1 in neuropathic pain may vary according to the brain region. In this study, we generated PAG\u2010specific and spinal cord\u2010specific GLT1 knockout mice. Nerve injury\u2010induced neuropathic pain was enhanced in spinal cord\u2010specific GLT1 knockout mice but alleviated in PAG\u2010specific GLT1 knockout mice. Thus, nerve injury may enhance glutamatergic neurotransmission from primary sensory neurons to the post\u2010synaptic dorsal horn following downregulation of GLT1 in the spinal cord and result in inadequate descending pain inhibition caused by GLT1 upregulation in the PAG, resulting in neuropathic pain. In addition, ceftriaxone upregulated GLT1 expression in the spinal cord, but not the PAG, of control mice and attenuated tactile hypersensitivity in nerve\u2010injured control mice but not in nerve\u2010injured spinal cord\u2010specific GLT1 knockout mice. Based on these results, the anti\u2010neuropathic pain effect of ceftriaxone is mediated by the upregulation of GLT1 expression in the spinal cord. Thus, selective upregulation of spinal GLT1 and\/or downregulation of GLT1 in the PAG represents a potentially novel strategy for the treatment of neuropathic pain.<\/jats:p>","DOI":"10.1002\/glia.23452","type":"journal-article","created":{"date-parts":[[2018,5,3]],"date-time":"2018-05-03T18:59:22Z","timestamp":1525373962000},"page":"1988-1998","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["<scp>R<\/scp>egion\u2010specific deletions of the glutamate transporter <scp>GLT<\/scp>1 differentially affect nerve injury\u2010induced neuropathic pain in mice"],"prefix":"10.1002","volume":"66","author":[{"given":"Zhuoyang","family":"Zhao","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Neuroscience, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), 1\u20105\u201045 Yushima Bunkyo\u2010ku Tokyo 113\u20108510 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Hiraoka","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuroscience, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), 1\u20105\u201045 Yushima Bunkyo\u2010ku Tokyo 113\u20108510 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuroscience, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), 1\u20105\u201045 Yushima Bunkyo\u2010ku Tokyo 113\u20108510 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6929-4228","authenticated-orcid":false,"given":"Kohichi","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuroscience, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), 1\u20105\u201045 Yushima Bunkyo\u2010ku Tokyo 113\u20108510 Japan"},{"name":"Center for Brain Integration Research (CBIR), TMDU, 1\u20105\u201045 Yushima Bunkyo\u2010ku Tokyo 113\u20108510 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,3]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2014.14"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2015.26"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-9-21"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.09.028"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-017-4802-7"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2006.10.008"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2015.08.010"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(94)90144-9"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.2"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1465-14.2014"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(00)00067-8"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pa.20.040180.002301"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22936"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12957"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3686-05.2006"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2008.12.009"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5583-12.2013"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2009.11.014"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.14581\/jer.16002"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws330"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.1391"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2011.01.014"},{"issue":"11","key":"e_1_2_6_24_1","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1101\/gad.14.11.1377","article-title":"Two lineage boundaries coordinate vertebrate apical ectodermal ridge formation","volume":"14","author":"Kimmel R. 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