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 Tozaki-Saitoh, Toshiyasu Imai, Yasushi Kuraishi, Makoto Tsuda, Kazuhide Inoue

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number32461
JournalScientific reports
Volume6
DOIs
Publication statusPublished - Aug 31 2016

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Purinergic P2X4 Receptors
Chronic Pain
Acute Pain
Pain
Down-Regulation
Microglia
Nociceptive Pain
Posterior Horn Cells
Hyperalgesia
Brain-Derived Neurotrophic Factor
Drug Discovery
Oral Administration
Cations
Spinal Cord
Up-Regulation
Adenosine Triphosphate

All Science Journal Classification (ASJC) codes

  • General

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A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain. / Matsumura, Yuta; Yamashita, Tomohiro; Sasaki, Atsushi; Nakata, Eriko; Kohno, Keita; Masuda, Takahiro; Tozaki-Saitoh, Hidetoshi; Imai, Toshiyasu; Kuraishi, Yasushi; Tsuda, Makoto; Inoue, Kazuhide.

In: Scientific reports, Vol. 6, 32461, 31.08.2016.

Research output: Contribution to journalArticle

Matsumura, Yuta ; Yamashita, Tomohiro ; Sasaki, Atsushi ; Nakata, Eriko ; Kohno, Keita ; Masuda, Takahiro ; Tozaki-Saitoh, Hidetoshi ; Imai, Toshiyasu ; Kuraishi, Yasushi ; Tsuda, Makoto ; Inoue, Kazuhide. / A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain. In: Scientific reports. 2016 ; Vol. 6.
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abstract = "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.",
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AB - 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.

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