Kyushu University Academic Staff Educational and Research Activities Database
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Kazuhide Inoue Last modified date:2018.10.26

Executive Vice President(Senior Vice President) / Trustee(Vice President)

Administration Post
Vice President

Department of Molecular and System Pharmacology .
Academic Degree
Country of degree conferring institution (Overseas)
Field of Specialization
Total Priod of education and research career in the foreign country
Research Interests
  • Research for the functions of purinergic receptors on neuropathic pain sugnalling
    keyword : ATP, purine, pain
  • The function of glia-neuron interaction for the mechanism of neuropathic pain through purinergic receptors.
    keyword : pain, ATP receptors
  • Finding the machanism of the regulation of the function of astrocyte-neuron interaction through extracellular ATP.
    keyword : ATP, astrocytes
Current and Past Project
  • To examine the mechanism of neuropathic pain.
Academic Activities
1. 井上和秀, 生理活性ヌクレオチド・ヌクレオシド In New薬理学, 南江堂, 田中千賀子、加藤隆一編、p.147-149, 2007.12.
2. Tsuda M and Inoue K., P2X receptors in Sensory Neurons. In The Nociceptive Membrane (Current Topics in Membrane, vol.57) Uhtaek Oh., Academic Press, London, p.277-310, 2006.04.
3. Inoue K, ATP receptors of microglia involved in pain. In Purinergic signaling in neuron-glia interaction (Novartis Foundation Symposium 276), John Wiley & Sons, Ltd, Chichester, p.263-281, 2006.04.
4. Inoue K., Chronic pain and microglia: the role of ATP. In Pathological pain:From molecular to clinical aspects (Novartis Foundation Symposium 261), John Wiley & Sons, Ltd, Chichester, p.263-281, 2004.01.
1. Inoue K, Purinergic systems in microglia., Cell Mol Life Sci, 65, 3074-3080, 2008.06.
1. Masuda Takahiro, Nao Nishimoto, Daisuke Tomiyama, Tsuyoshi Matsuda, Hidetoshi Saitoh, Tomohiko Tamura, Shinichi Kohsaka, TSUDA MAKOTO, Kazuhide Inoue, IRF8 is a transcriptional determinant for microglial motility. , Purinergic Signal., [Epub ahead of print], 2014.05.
2. Masuda Takahiro, Shosuke Iwamoto, Ryohei Yoshinaga, Hidetoshi Saitoh, A. Nishiyama, T. W. Mak, T. Tamura, TSUDA MAKOTO, Kazuhide Inoue, Transcription factor IRF5 drives P2X4R+ reactive microglia gating neuropathic pain. , Nat Commun., doi: 10.1038/ncomms4771., 13;5:3771. , 2014.05.
3. Katsuyuki Matsushita, Chinami Kojima, Hidetoshi Saitoh, TSUDA MAKOTO, Kazuhide Inoue, Sumio Hoka, C-C chemokine receptor type 5 is an important pathological regulator in the development and maintenance of neuropathic pain. , Anesthesiology, DOI: 10.1097 /ALN.0000000000000190, 120, 6, 1491-1503, [Epub ahead of print], 2014.02, Background: Chemokine family are revealed to be involved in the pathogenesis of neuropathic pain. In this study, we investigated the role of C-C chemokine ligand 3 (CCL3) and its receptors C-C chemokine receptor type 1 (CCR1) and C-C chemokine receptor type 5 (CCR5) in neuropathic pain.
Materials and Methods: Adult male Wistar rats were used. Spinal nerve injury model was used as a model of neuropathic pain. CCL3 neutralizing antibody, CCR1 antagonist or CCR5 antagonist were administered. Von Frey test and hot plate test were applied to evaluate the neuropathic pain behavior. Real-time quantitative RT-PCR, in situ hybridization, immunohistochemistry were also performed to clarify molecular mechanisms.
Results: Expression levels of CCL3 and CCR5 mRNA in the spinal cord were upregulated after nerve injury. CD11b/c positive microglia were suggested to be responsible for these upregulation. Single intrathecal administration of recombinant CCL3 produced biphasic tactile allodynia-like behavior. The first phase reaction was suppressed by CCR1 antagonist pretreatment, and the second phase reaction was suppressed by CCR5 antagonist pretreatment. Intrathecal injection of CCL3 neutralizing antibody or CCR5 antagonist, successfully suppressed the development of tactile allodynia. Intrathecal injection of CCL3 neutralizing antibody or CCR5 antagonist could reverse the established tactile allodynia. CCR1 antagonist had transient effect to reverse tactile allodynia. Furthermore, oral administration of CCR5 antagonist was effective to established tactile allodynia.
Conclusions: Pharmacological blockade of CCR5 was effective in the development and maintenance of neuropathic pain. Thus, CCR5 antagonist may be a potential new drug for the treatment of neuropathic pain..
4. Nakaya Michio, Tajima M, Kosako H, Nakaya T, Hashimoto A, Watari K, Nishihara H, Ohba M, Komiya S, Tani N, Motohiro Nishida, Taniguchi H, Sato Y, Matsumoto M, TSUDA MAKOTO, Kuroda M, Kazuhide Inoue, Hitoshi Kurose, GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance., Nat Commun., doi: 10.1038/ncomms2540., 4:1532., 2013.02.
5. Sun L, Wu Z, Yoshinori Hayashi, Peters C, TSUDA MAKOTO, Kazuhide Inoue, Hiroshi Nakanishi, Microglial cathepsin B contributes to the initiation of peripheral inflammation-induced chronic pain., J Neurosci, 32(33):11330-42., 2012.08.
6. Masuda Takahiro, TSUDA MAKOTO, Ryohei Yoshinaga, Hidetoshi Saitoh, K. Ozato, T. Tamura, Kazuhide Inoue, IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype., Cell Rep., doi: 10.1016/j.celrep.2012.02.014., 1(4):334-40, 2012.04, Microglia become activated by multiple types of damage in the nervous system and play essential roles in neuronal pathologies. However, how microglia transform into reactive phenotypes is poorly understood. Here, we identify the transcription factor interferon regulatory factor 8 (IRF8) as a critical regulator of reactive microglia. Within the spinal cord, IRF8 expression was normally low; however, the expression was markedly upregulated in microglia, but not in neurons or astrocytes, after peripheral nerve injury (PNI). IRF8 overexpression in cultured microglia promoted the transcription of genes associated with reactive states; conversely, IRF8 deficiency prevented these gene expressions in the spinal cord following PNI. Furthermore, IRF8-deficient mice were resistant to neuropathic pain, a common sequela of PNI, and transferring IRF8-overexpressing microglia spinally to normal mice produced pain. Therefore, IRF8 may activate a program of gene expression that transforms microglia into a reactive phenotype. Our findings provide a newly observed mechanism for microglial activation..
7. Y. Hayashi, K. Kawaji, L. Sun, X. Zhang, K. Koyano, T. Yokoyama, S.Kohsaka, K. Inoue, and H. Nakanishi., Microglial Ca2+-activated K+ Channels Are Possible Molecular Targets for the Analgesic Effects of S-ketamine on Neuropathic Pain., J.Neurosci, 10.1523/JNEUROSCI.4152-11.2011, 31, 48, 17370-17382, 2011.11.
8. Biber K, Tsuda M, Saitoh-Tozaki H, Tsukamoto K, Toyomitsu E, Masuda T, Boddeke H, Inoue K., Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development., EMBO J, 30:1864-73, 2011.05.
9. M. Nishida, M. Ogushi, R. Suda, M. Toyotaka, S. Saiki, N. Kitajima, M. Nakaya, K.-M. Kim, T. Ide, Y. Sato, K. Inoue, and H. Kurose., Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y2 receptor stimulation through S-nitrosylation of NF-κB, PNAS, 108(16):6662-7, 2011.04.
10. M. Tsuda, Y. Kohro, T. Yano, T. Tsujikawa, J. Kitano, H. Tozaki-Saitoh, S. Koyanagi, S. Ohdo, R-R Ji, M. W. Salter, K. Inoue., JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. , Brain, 134(4): 1127-1139, 2011.04.
11. M. Tsuda*, T. Masuda*, J. Kitano, H. Shimoyama, H. Tozaki-Saitoh, K. Inoue. *equally contributed., IFN-γ receptor signaling mediates spinal microglia activation driving neuropathic pain. , Pro.Natl.Acad.Sci.USA , 106(19):8032-7, 2009.05.
12. Y. Shinozaki, K. Sumitomo, M. Tsuda, S. Koizumi, K. Inoue and K. Torimitsu. , Direct observation of ATP-induced conformational changes in single P2X4 receptors.
, PLoS Biology , 2009 May 5;7(5):e103. [Epub ahead of print]
, 2009.05.
13. H. Tozaki-Saitoh1, M. Tsuda, H. Miyata, K. Ueda, S. Kohsaka, K. Inoue. , P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. , J.Neurosci., 28:4949-56, 2008.05.
14. Coull JAM, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y, BDNF from microglia mediates the shift in neuronal anion gradient that underlies neuropathic pain., Nature, 10.1038/nature04223, 438, 7070, 1017-1021, 438, 1017-1021, 2005.04.
15. Koizumi S, Fujishita K, Tsuda M, Shigemoto-Mogami Y, Kita A, Inoue K., Dynamic inhibition of excitatory synaptic transmission by astrocyte-derived ATP in hippocampal cultures., Pro Nat Acad Sci USA, 10.1073/pnas.1834448100, 100, 19, 11023-11028, 100, 11023-11028, 2003.04.
16. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K., P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury., Nature, 10.1038/nature01786, 424, 6950, 778-783, 424, 778-783, 2003.04.
1. Kazuhide Inoue, Purinergic Regulation of Microglia in Neuropathic Pain, Keystone Symposia Conference Purinergic Signaling, 2016.01.
2. Kazuhide Inoue, The role of microglia in neuropathic pain mechanism., NEA_ASIAHORCsシンポジウム, 2015.11.
3. Kazuhide Inoue, Onset Mechanisms of Neuropathic Pain., 第63回国際歯科研究学会日本部会(JADR)学術大会, 2015.10.
4. Miho Shiratori-Hayashi, Keisuke Koga, Hidetoshi Tozaki-Saitoh, Yuta Kohro, Junichi Hachisuka, Hideyuki Okano, Masutaka Furue, Kazuhide Inoue, TSUDA MAKOTO, STAT3-dependent reactive astrocytes in the spinal dorsal horn contribute to the maintenance of chronic itch in mice, Neuroscience 2015, 2015.10.
5. Kazuhide Inoue, P2X4 of microglia in neuropathic pain., Purine 2015, 2015.07.
6. Kazuhide Inoue, Glial cell implication on pain modulation., The 8th Igakuken International Symposium on “Pain Modulation and Opioid Functions”, 2014.09.
7. Kazuhide Inoue, The role of microglia in neuropathic pain., The 12th Asian-Pacific Society for Neurochemistry, 2014.08.
8. Kazuhide Inoue, The role of microglial purinergic signaling in neuropathic pain., the 17th World Congress of Basic and Clinical Pharmacology, 2014.07.
9. Kazuhide Inoue, Gene regulation in microglia in neuropathic pain., 29th CINP WORLD CONGRESS OF NEUROPSYCHOPHARMACOLOGY, 2014.06.
10. Kazuhide Inoue, Activation of spinal microglia causing neuropathic pain., The 22nd International Symposium on Molecular Cell Biology of Macrophages, 2014.06.
11. Kazuhide Inoue, The role of microglia in neuropathic pain after nerve injury., the 1st EMBO Workshop -Microglia: Sculptors of the brain, 2014.03, Neuropathic pain after peripheral nerve injury (PNI) is a highly debilitating chronic pain resistant to currently available medicines including morphine and NSAIDs (non-steroidal anti-Inflammatory drugs). We reported that activated microglia overexpressed P2X4 receptors after PNI which release brain-derived neurotrophic factor (BDNF). BDNF evokes a collapse of their transmembrane anion gradient in the secondary neurons of dorsal hone resulting in hyper-excitability of the neurons (Nature, 2003 & 2005). Recently, we found that interferon-γ plays an important role in nerve injury-induced tactile allodynia and activation of microglia. We also found that CCL2, ligands for CCR2, increased P2X4R expression in microglial surface fraction. Moreover, chemokine CCL21 was rapidly expressed in small-sized DRG neurons after PNI and transported into the sensory nerve endings through the dorsal root. CCL21 deficient mice failed to overexpression of P2X4R in microglia and did not evoke tactile allodynia. Also, neutralizing antibodies for CCL21 inhibited tactile allodynia in wild type mice. The result indicates that CCL21 from damaged DRG neurons causes P2X4 overexpression in activated spinal microglia resulting in neuropathic pain.
Various molecules in microglia are related to neuropathic pain. However, how microglia regulate the expression of these molecules is poorly understood. Then, we examined the transcription factor interferon-regulatory factor 8 (IRF8) as a critical regulator of the genes in microglia. IRF8 expression was markedly upregulated in microglia, but not in neurons or astrocytes, after nerve injury. IRF8 overexpression in cultured microglia promoted the transcription of genes associated with reactive states. IRF8 deficiency prevented these gene expressions in the spinal cord and neuropathic pain following PNI. Therefore, IRF8 may activate a program of gene expression that transforms microglia into a reactive phenotype..
12. Kazuhide Inoue, P2X4 blockers: New drugs for the neuropathic pain., Asian Federation for Pharmaceutical Sciences 2013, 2013.11.
13. Kazuhide Inoue, Microglia causing neuropathic pain after nerve injury., the IUPS 2013 Congress, 2013.07.
14. Kazuhide Inoue, Role of PAF receptor in pro-inflammatory cytokine expression in the dorsal root ganglion in a neuropathic pain model., The 14th World Congress on Pain., 2012.08.
15. Kazuhide Inoue, Microglia in pain signalling., The 29th Naito Conference: Glia World, 2010.10.