A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain

Yuta Matsumura, Tomohiro Yamashita, Atsushi Sasaki, Eriko Nakata, Keita Kohno, Takahiro Masuda, Hidetoshi Saitoh, Toshiyasu Imai, Yasushi Kuraishi, Makoto Tsuda, Kazuhide Inoue

研究成果: ジャーナルへの寄稿学術誌査読

96 被引用数 (Scopus)


Accumulating evidence indicates that purinergic P2X4 receptors (P2X4R: cation channels activated by extracellular ATP) expressed in spinal microglia are crucial for pathological chronic pain caused by nerve damage, suggesting a potential target for drug discovery. We identified NP-1815-PX (5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1, 2-b][1,4]diazepine-2,4(3H,5H)-dione) as a novel antagonist selective for P2X4R with high potency and selectivity compared with other P2XR subtypes. In in vivo 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+/Cl- 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.

ジャーナルScientific reports
出版ステータス出版済み - 8月 31 2016

!!!All Science Journal Classification (ASJC) codes

  • 一般


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