title: Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain.
abstract: Activation of purinergic receptors in the spinal cord by extracellular ATP is essential for neuropathic hypersensitivity after peripheral nerve injury (PNI). However, the cell type responsible for releasing ATP within the spinal cord after PNI is unknown. Here we show that PNI increases expression of vesicular nucleotide transporter (VNUT) in the spinal cord. Extracellular ATP content ([ATP]e) within the spinal cord was increased after PNI, and this increase was suppressed by exocytotic inhibitors. Mice lacking VNUT did not show PNI-induced increase in [ATP]e and had attenuated hypersensitivity. These phenotypes were recapitulated in mice with specific deletion of VNUT in spinal dorsal horn (SDH) neurons, but not in mice lacking VNUT in primary sensory neurons, microglia or astrocytes. Conversely, ectopic VNUT expression in SDH neurons of VNUT-deficient mice restored PNI-induced increase in [ATP]e and pain. Thus, VNUT is necessary for exocytotic ATP release from SDH neurons which contributes to neuropathic pain.
authors: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|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 Breisacherstraße 64, Freiburg 79106, Germany.|JST, CREST, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Takahiro
authors: T
authors: Masuda
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: Yui
authors: Y
authors: Ozono
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: Satsuki
authors: S
authors: Mikuriya
authors: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Yuta
authors: Y
authors: Kohro
authors: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|JST, CREST, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Hidetoshi
authors: 0000-0003-0423-2143
authors: H
authors: Tozaki-Saitoh
authors: Institute for Innovation, Ajinomoto Co., Inc., Kawasaki 210-8681, Japan.|Department of Nutritional Science and Food Safety, Tokyo University of Agriculture, Tokyo 156-8502, Japan.
authors: Ken
authors: K
authors: Iwatsuki
authors: Institute for Innovation, Ajinomoto Co., Inc., Kawasaki 210-8681, Japan.
authors: Hisayuki
authors: H
authors: Uneyama
authors: Institute for Innovation, Ajinomoto Co., Inc., Kawasaki 210-8681, Japan.
authors: Reiko
authors: R
authors: Ichikawa
authors: Program in Neurosciences &Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.|Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors: Michael W
authors: 0000-0001-6897-6585
authors: MW
authors: Salter
authors: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Department of Life Innovation, 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.|JST, CREST, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Kazuhide
authors: K
authors: Inoue
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D004195:Disease Models, Animal; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D009437:Neuralgia / Q000209:etiology / Q000473:pathology*; D033704:Nucleotide Transport Proteins / Q000235:genetics / Q000378:metabolism*; D059348:Peripheral Nerve Injuries / Q000209:etiology / Q000473:pathology*; D020671:Posterior Horn Cells / Q000378:metabolism / Q000473:pathology*; D011984:Sensory Receptor Cells / Q000378:metabolism; D013744:Tetanus Toxin / Q000494:pharmacology
chemical_list: D033704:Nucleotide Transport Proteins; C578984:Slc17a9 protein, mouse; D013744:Tetanus Toxin; D000255:Adenosine Triphosphate