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We identified NP-1815-PX (5-[3-(5-thioxo-<jats:italic>4H<\/jats:italic>-[1,2,4]oxadiazol-3-yl)phenyl]-<jats:italic>1H<\/jats:italic>-naphtho[1, 2-b][1,4]diazepine-2,4(<jats:italic>3H<\/jats:italic>,<jats:italic>5H<\/jats:italic>)-dione) as a novel antagonist selective for P2X4R with high potency and selectivity compared with other P2XR subtypes. In<jats:italic>in vivo<\/jats:italic>assay for acute and chronic pain, intrathecal administration of NP-1815-PX produced an anti-allodynic effect in mice with traumatic nerve damage without affecting acute nociceptive pain and motor function (although its oral administration did not produce the effect). Furthermore, in a mouse model of herpetic pain, P2X4R upregulation in the spinal cord exclusively occurred in microglia and intrathecal NP-1815-PX suppressed induction of mechanical allodynia. This model also showed K<jats:sup>+<\/jats:sup>\/Cl<jats:sup>\u2212<\/jats:sup>cotransporter 2 (KCC2) downregulation, which is implicated in dorsal horn neuron hyperexcitability; this downregulation was restored by intrathecal treatment with NP-1815-PX or by interfering with brain-derived neurotrophic factor (BDNF) signaling, a P2X4R-activated microglial factor implicated in KCC2 downregulation. Taken together, the newly developed P2X4R antagonist NP-1815-PX produces anti-allodynic effects in chronic pain models without altering acute pain sensitivity, suggesting that microglial P2X4R could be an attractive target for treating chronic pain.<\/jats:p>","DOI":"10.1038\/srep32461","type":"journal-article","created":{"date-parts":[[2016,8,31]],"date-time":"2016-08-31T15:41:45Z","timestamp":1472658105000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":131,"title":["A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain"],"prefix":"10.1038","volume":"6","author":[{"given":"Yuta","family":"Matsumura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Yamashita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eriko","family":"Nakata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keita","family":"Kohno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Masuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetoshi","family":"Tozaki-Saitoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyasu","family":"Imai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Kuraishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Tsuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhide","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,8,31]]},"reference":[{"key":"BFsrep32461_CR1","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/0304-3959(86)90089-8","volume":"25","author":"JD Loeser","year":"1986","unstructured":"Loeser, J. 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