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The presence of prediabetic neuropathic pain (PDNP) poses challenges to the management of individuals with prediabetes. However, the mechanisms underlying this pain remain unclear. This study aims to investigate the underlying mechanism and identify potential therapeutic targets of PDNP. A prediabetic animal model induced by a high\u2010energy diet exhibits both mechanical allodynia and thermal hyperalgesia. Furthermore, hyperexcitability and decreased potassium currents are observed in the dorsal root ganglion (DRG) neurons of these rats. TREK1 and TREK2 channels, which belong to the two\u2010pore\u2010domain K\n                    <jats:sup>+<\/jats:sup>\n                    channel (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>2P<\/jats:sub>\n                    ) family and play an important role in controlling cellular excitability, are downregulated in DRG neurons. Moreover, this alteration is modulated by Sortilin, a molecular partner that modulates the expression of TREK1. The overexpression of Sortilin negatively affects the expression of TREK1 and TREK2, leading to increased neuronal excitability in the DRG and enhanced peripheral pain sensitivity in rats. Moreover, the downregulation of Sortilin or activation of TREK1 and TREK2 channels by genetic or pharmacological approaches can alleviate PDNP. Therefore, targeting the Sortilin\u2010mediated TREK1\/2 pathway may provide a therapeutic approach for ameliorating PDNP.\n                  <\/jats:p>","DOI":"10.1002\/advs.202310295","type":"journal-article","created":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T15:54:25Z","timestamp":1713282865000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Sortilin\u2010Mediated Inhibition of TREK1\/2 Channels in Primary Sensory Neurons Promotes Prediabetic Neuropathic Pain"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0405-9774","authenticated-orcid":false,"given":"Wei","family":"Sun","sequence":"first","affiliation":[{"name":"Institute for Biomedical Sciences of Pain Tangdu Hospital The Fourth Military Medical University  Xi'an Shaanxi Province 710038 P. R. 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