title: A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain.
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.
authors: Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Yuta
authors: Y
authors: Matsumura
authors: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Tomohiro
authors: T
authors: Yamashita
authors: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors: Atsushi
authors: A
authors: Sasaki
authors: Discovery Research Laboratories, Nippon Chemiphar Co., Ltd., Misato, Saitama 341-0005, Japan.
authors: Eriko
authors: E
authors: Nakata
authors: Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Keita
authors: K
authors: Kohno
authors: Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Institute of Neuropathology, University of Freiburg, Neurozentrum, Breisacherstr. 64, Freiburg 79106, Germany.
authors: Takahiro
authors: T
authors: Masuda
authors: Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Hidetoshi
authors: H
authors: Tozaki-Saitoh
authors: Discovery Research Laboratories, Nippon Chemiphar Co., Ltd., Misato, Saitama 341-0005, Japan.
authors: Toshiyasu
authors: T
authors: Imai
authors: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors: Yasushi
authors: Y
authors: Kuraishi
authors: Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Makoto
authors: M
authors: Tsuda
authors: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Kazuhide
authors: K
authors: Inoue
mesh_terms: D000818:Animals; D001381:Azepines; D004195:Disease Models, Animal; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D010069:Oxadiazoles; D010146:Pain / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000473:pathology; D058920:Purinergic P2X Receptor Antagonists / Q000008:administration & dosage*; D058848:Receptors, Purinergic P2X4 / Q000235:genetics*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology
chemical_list: D001381:Azepines; C000627125:NP-1815-PX; D010069:Oxadiazoles; D058920:Purinergic P2X Receptor Antagonists; D058848:Receptors, Purinergic P2X4