TY - JOUR
T1 - Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain
AU - Masuda, Takahiro
AU - Ozono, Yui
AU - Mikuriya, Satsuki
AU - Kohro, Yuta
AU - Tozaki-Saitoh, Hidetoshi
AU - Iwatsuki, Ken
AU - Uneyama, Hisayuki
AU - Ichikawa, Reiko
AU - Salter, Michael W.
AU - Tsuda, Makoto
AU - Inoue, Kazuhide
N1 - Funding Information:
This work was supported by grants from the Japan Society for the Promotion of Science through the Ministry of Education, Culture, Sports, Science and Technology of Japan (T.M., M.T., K.I., KAKENHI Grant Numbers 25117013, 15H02522) and from the Japan Science and Technology Agency (JST) through the Core Research for Evolutional Science and Technology (CREST) program (K.I.), from Kyushu University (Progress 100) (M.T.), the Research Project on Elucidation of Chronic Pain from Japan Agency for Medical Research and Development (M.T.), and the Toray Science Foundation (M.T.), and was also supported by Platform for Drug Discovery, Informatics and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan (K.I.). We appreciate the technical support from the Research Support Center, Graduate School of Medical Sciences, Kyushu University.
Publisher Copyright:
© 2016 The Author(s).
PY - 2016/8/12
Y1 - 2016/8/12
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms12529
DO - 10.1038/ncomms12529
M3 - Article
C2 - 27515581
AN - SCOPUS:84982261438
SN - 2041-1723
VL - 7
JO - Nature communications
JF - Nature communications
M1 - 12529
ER -