{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T06:23:33Z","timestamp":1787207013577,"version":"build-2736575974"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100016077","name":"Dongguan Science and Technology Bureau","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100016077","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Diabetic neuropathic pain (DNP) is a disabling complication of diabetes mellitus and is closely associated with impaired inhibitory neurotransmission and neuroimmune activation. Although GABAergic dysfunction has been implicated in neuropathic pain, the relationship between peripheral transcriptomic signatures, central transcriptional alterations, and the therapeutic effects of GABA receptor modulation remains incompletely understood. This study integrated human peripheral blood transcriptomic reanalysis, mouse whole-brain RNA-seq, behavioral assessment, RT-qPCR, and molecular docking to investigate DNP- associated molecular alterations and the potential mechanism of baclofen.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Peripheral blood transcriptome data from diabetic peripheral neuropathy patients and healthy controls were reanalyzed using the GSE95849 dataset as a DPN\/DNP-related human transcriptomic resource. Differential expression analysis, custom preranked GSEA, ssGSEA, and curated heatmap analysis were performed to identify immune-inflammatory and synaptic\/GABAergic-related signatures. A streptozotocin-induced DNP mouse model was established, and DNP mice received systemic baclofen treatment. Mechanical allodynia, thermal hyperalgesia, grip strength, and motor coordination were assessed. Whole-brain RNA-seq was performed in control, DNP, and baclofen-treated DNP mice to evaluate central transcriptional alterations and treatment-associated pathway modulation. RT-qPCR was used to measure brain\n                      <jats:italic>Gabra1<\/jats:italic>\n                      expression, and molecular docking was performed to evaluate the predicted binding mode of baclofen with GABA receptors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Reanalysis of human peripheral blood transcriptomes revealed enhanced immune-inflammatory activation and reduced synaptic\/GABAergic-related pathway activity in the DPN\/DNP-related human peripheral blood dataset. In DNP mice, baclofen treatment significantly alleviated mechanical allodynia and thermal hyperalgesia and partially improved neuromuscular performance without impairing motor coordination. Whole-brain RNA-seq showed that DNP mice exhibited significant negative enrichment of GABAergic signaling and inhibitory synapse signatures, together with positive enrichment of neuroinflammation\/NF-\n                      <jats:italic>\u03ba<\/jats:italic>\n                      B and glial activation-related signatures. Baclofen treatment showed partial and directional modulation of these DNP-associated transcriptional alterations, including a shift toward restoration of inhibitory\/synaptic signatures and attenuation of neuroinflammatory pathway activity. RT-qPCR further showed that baclofen increased the DNP-suppressed brain expression of\n                      <jats:italic>Gabra1<\/jats:italic>\n                      . Molecular docking supported the preferential interaction of baclofen with the GABA\n                      <jats:sub>B<\/jats:sub>\n                      receptor, including a predicted salt bridge with Arg162 within the Venus Flytrap domain.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      DNP is associated with convergent peripheral and central transcriptomic alterations characterized by immune-inflammatory activation and reduced inhibitory\/synaptic pathway activity. Baclofen alleviates neuropathic hypersensitivity and is associated with partial, pathway-level modulation of DNP-related brain transcriptional changes, with\n                      <jats:italic>Gabra1<\/jats:italic>\n                      restoration and GABA\n                      <jats:sub>B<\/jats:sub>\n                      receptor binding providing additional mechanistic support. These findings suggest that GABA\n                      <jats:sub>B<\/jats:sub>\n                      receptor modulation may contribute to restoring inhibitory balance and attenuating neuroinflammatory activation in DNP.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1917799","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T05:26:14Z","timestamp":1787203574000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptomic and molecular evidence for baclofen-associated modulation of inhibitory synaptic and neuroinflammatory pathways in diabetic neuropathic pain"],"prefix":"10.3389","volume":"17","author":[{"given":"Kaisheng","family":"Ye","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital of Jinan University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Binhaiwan Central Hospital of Dongguan","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haishao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Binhaiwan Central Hospital of Dongguan","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sizhuang","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital of Jinan University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangyu","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Heyou International Hospital","place":["Foshan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"B1","first-page":"2010","volume-title":"Fastqc: A Quality Control Tool for High Throughput Sequence Data","author":"Andrews","year":"2010"},{"key":"B2","doi-asserted-by":"publisher","first-page":"D991","DOI":"10.1093\/nar\/gks1193","article-title":"NCBI GEO: archive for functional genomics data sets\u2013update","volume":"41","author":"Barrett","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The protein data bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/j.pharmthera.2006.03.006","article-title":"Molecular diversity, trafficking and subcellular localization of GABAB receptors","volume":"110","author":"Bettler","year":"2006","journal-title":"Pharmacol. & Ther."},{"key":"B5","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.ebiom.2018.03.019","article-title":"GABA regulates release of inflammatory cytokines from peripheral blood mononuclear cells and CD4+ T cells and is immunosuppressive in type 1 diabetes","volume":"30","author":"Bhandage","year":"2018","journal-title":"EBioMedicine"},{"key":"B6","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/1744-8069-10-26","article-title":"A simplified up-down method (SUDO) for measuring mechanical nociception in rodents using von Frey filaments","volume":"10","author":"Bonin","year":"2014","journal-title":"Mol. 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