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TSUDA MAKOTO Last modified date:2022.05.30

Professor / Department of Molecular and System Pharmacology
Department of Pharmaceutical Health Care and Sciences
Faculty of Pharmaceutical Sciences

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Work in my laboratory is primarily directed to elucidating glia-neuron interactions in the spinal cord and brain and to understanding the cellular and molecular mechanisms of pain and itch signaling (in particular pathological chronic pain and itch). Our work employs several cutting-edge genetic tools to manipulate the specific type of cells to determine how identifiable populations of neurons and glial cells contribute to pain and itch behaviors in a causal manner. We also complementally use electrophysiology and cellular functional imaging (in vitro and in vivo) to measure activity of neurons and glial cells. From these studies, we devise strategies for new types of pain and itch relieving medications. .
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Field of Specialization
ORCID(Open Researcher and Contributor ID)
Outline Activities
Outline of research
Molecular and cellular mechanisms in the peripheral and central nervous system underlying chronic pain and itch focusing on the role of glial cells.

Pharmacology, Seminar, Medicine, Neuropharmacology
Research Interests
  • Molecular and cellular mechanisms of itch
    keyword : itch, spinal cord, neurons, glia, primary afferent sensory neurons
  • Studies on mechanisms underlying the development and maintenance of intractable pain
    keyword : neuropathic pain, ATP receptors, intracellular signal transduction, glial cells
Academic Activities
1. Toulme E, Tsuda M, Khakh BS, Inoue K, On the role of ATP-gated P2X receptors in acute, inflammatory and neuropathic pain, CRC Press, 2009.11.
2. M. Tsuda, K. Inoue, The nociceptive membrane, Current Topics in Membrane 57, Chapter 9. P2X receptors in sensory neurons., Elsevier, pp277-310, (2006), 2006.09.
1. Makoto Tsuda, Microglia-Mediated Regulation of Neuropathic Pain: Molecular and Cellular Mechanisms, 10.1248/bpb.b19-00715 , 2019.12.
2. Makoto Tsuda, Microglia-mediated regulation of neuropathic pain
Molecular and cellular mechanisms
, Biological and Pharmaceutical Bulletin, 10.1248/bpb.b19-00715, 2019.01, Pain is a defense system that responds rapidly to harmful internal and external stimuli through the somatosensory neuronal pathway. However, damage to the nervous system through cancer, diabetes, infection, autoimmune disease, chemotherapy or trauma often leads to neuropathic pain, a debilitating chronic pain condition. Neuropathic pain is not simply a temporal continuum of acute nociceptive signals from the periphery, but rather due to pathologically altered functions in the nervous system, which shift the net neuronal excitatory balance toward excitation. Although alterations were long thought to be a result of changes in neurons, but an increasing body of evidence over the past decades indicates the necessity and sufficiency of microglia, the tissue-resident macrophages of the spinal cord and brain, for nerve injury-induced malfunction of the nervous system. In this review article, I describe our current understanding of the molecular and cellular mechanisms underlying the role of microglia in the pathogenesis of neuropathic pain and discuss the therapeutic potential of microglia from recent advances in the development of new drugs targeting microglia..
3. Inoue K, Tsuda M, Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential., Nat Rev Neurosci, 10.1038/nrn.2018.2, 2018.03, Acute nociceptive pain is a key defence system that enables the detection of danger signals that threaten homeostasis and survival. However, chronic pain (such as the neuropathic pain that occurs after peripheral nerve injury) is not simply a consequence of the continuity of acute nociceptive signals but rather of maladaptive nervous system function. Over recent decades, studies have provided evidence for the necessity and sufficiency of microglia for the alterations in synaptic remodelling, connectivity and network function that underlie chronic pain and have shed light on the underlying molecular and cellular mechanisms. It is also becoming clear that microglia have active roles in brain regions important for the emotional and memory-related aspects of chronic pain. Recent advances in the development of new drugs targeting microglia and the establishment of new sources of human microglia-like cells may facilitate translation of these findings from bench to bedside..
4. TSUDA MAKOTO et al., Microglial regulation of neuropathic pain, J Pharmacol Sci, 2013.10.
5. TSUDA MAKOTO, Beggs S, Salter MW, Kazuhide Inoue, Microglia and intractable chronic pain, Glia, 2013.01.
6. Tsuda M, Tozaki-Saitoh H, Inoue K., Purinergic system, microglia and neuropathic pain., Curr Opin Pharmacol., 2012.02.
7. Inoue K, Tsuda M, Microglia and neuropathic pain., Glia, 2009.11.
8. Tsuda M, Inoue K, Salter MW., Neuropathic pain and spinal microglia: a big problem from molecules in "small" glia., Trends Neurosci. 2005 Feb;28(2):101-7., 2005.02.
1. Ryoichi Tashima, Keisuke Koga, Yu Yoshikawa, Misuzu Sekine, Moeka Watanabe, Hidetoshi Tozaki-Saitoh, Hidemasa Furue, Toshiharu Yasaka, Makoto Tsuda, A subset of spinal dorsal horn interneurons crucial for gating touch-evoked pain-like behavior., Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.2021220118, 118, 3, 2021.01, A cardinal, intractable symptom of neuropathic pain is mechanical allodynia, pain caused by innocuous stimuli via low-threshold mechanoreceptors such as Aβ fibers. However, the mechanism by which Aβ fiber-derived signals are converted to pain remains incompletely understood. Here we identify a subset of inhibitory interneurons in the spinal dorsal horn (SDH) operated by adeno-associated viral vectors incorporating a neuropeptide Y promoter (AAV-NpyP+) and show that specific ablation or silencing of AAV-NpyP+ SDH interneurons converted touch-sensing Aβ fiber-derived signals to morphine-resistant pain-like behavioral responses. AAV-NpyP+ neurons received excitatory inputs from Aβ fibers and transmitted inhibitory GABA signals to lamina I neurons projecting to the brain. In a model of neuropathic pain developed by peripheral nerve injury, AAV-NpyP+ neurons exhibited deeper resting membrane potentials, and their excitation by Aβ fibers was impaired. Conversely, chemogenetic activation of AAV-NpyP+ neurons in nerve-injured rats reversed Aβ fiber-derived neuropathic pain-like behavior that was shown to be morphine-resistant and reduced pathological neuronal activation of superficial SDH including lamina I. These findings suggest that identified inhibitory SDH interneurons that act as a critical brake on conversion of touch-sensing Aβ fiber signals into pain-like behavioral responses. Thus, enhancing activity of these neurons may offer a novel strategy for treating neuropathic allodynia..
2. Keisuke Koga, Ryo Yamagata, Keita Kohno, Takuya Yamane, Miho Shiratori-Hayashi, Yuta Kohro, Hidetoshi Tozaki-Saitoh, Makoto Tsuda, Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor, Journal of Allergy and Clinical Immunology, 10.1016/j.jaci.2019.09.034, 145, 1, 183-191.e10, 2020.01, Background: Chronic itch is a highly debilitating symptom among patients with inflammatory skin diseases. Recent studies have revealed that gastrin-releasing peptide (GRP) and its receptor (gastrin-releasing peptide receptor [GRPR]) in the spinal dorsal horn (SDH) play a central role in itch transmission. Objective: We aimed to investigate whether GRP-GRPR signaling is altered in SDH neurons in a mouse model of chronic itch and to determine the potential mechanisms underlying these alterations. Methods: Patch-clamp recordings from enhanced green fluorescent protein (EGFP)–expressing (GRPR+) SDH neurons were used to examine GRP-GRPR signaling in spinal cord slices obtained from Grpr-EGFP mice. Immunohistochemical, genetic (gene expression and editing through adeno-associated virus vectors), and behavioral approaches were also used for in vivo experiments. Results: We observed potentiation of GRP-evoked excitation in the GRPR+ SDH neurons of mice with contact dermatitis, without concomitant changes in GRPR expression. Interestingly, increases in excitation were attenuated by suppressing the reactive state of SDH astrocytes, which are known to be reactive in patients with chronic itch conditions. Furthermore, CRISPR-Cas9–mediated astrocyte-selective in vivo editing of a gene encoding lipocalin-2 (LCN2), an astrocytic factor implicated in chronic itch, suppressed increases in GRP-induced excitation of GRPR+ neurons, repetitive scratching, and skin damage in mice with contact dermatitis. Moreover, LCN2 potentiated GRP-induced excitation of GRPR+ neurons in normal mice. Conclusion: Our findings indicate that, under chronic itch conditions, the GRP-induced excitability of GRPR+ SDH neurons is enhanced through a non–cell-autonomous mechanism involving LCN2 derived from reactive astrocytes..
3. Tashima R, Koga K, Sekine M, Kanehisa K, Kohro Y, Tominaga K, Matsushita K, Tozaki-Saitoh H, Fukazawa Y, Inoue K, Yawo H, Furue H, Tsuda M, Optogenetic activation of non-nociceptive Aβ fibers induces neuropathic pain-like sensory and emotional behaviors after nerve injury in rats., eNeuro, 10.1523/ENEURO.0450-17.2018, 5, ENEURO.0450-17.2018, 2018.02.
4. Masuda T et al., Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain, Nat Commun, 7, 12529, 2016.08.
5. Tashima R et al., Bone marrow-derived cells in the population of spinal microglia after peripheral nerve injury, Sci Rep, 6, 23701, 2016.03.
6. Yuta Kohro et al., A new minimally-invasive method for microinjection into the mouse spinal dorsal horn, Sci Rep, 5, 14306, 2015.09.
7. Miho Shiatori-Hayashi et al., STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch, NATURE MEDICINE, 10.1038/nm.3912, 21, 8, 927-931, 2015.08, Chronic itch is an intractable symptom of inflammatory skin diseases, such as atopic and contact dermatitis. Recent studies have revealed neuronal pathways selective for itch, but the mechanisms by which itch turns into a pathological chronic state are poorly understood. Using mouse models of atopic and contact dermatitis, we demonstrate a long-term reactive state of astrocytes in the dorsal horn of the spinal segments that corresponds to lesioned, itchy skin. We found that reactive astrogliosis depended on the activation of signal transducer and activator of transcription 3 (STAT3). Conditional disruption of astrocytic STAT3 suppressed chronic itch, and pharmacological inhibition of spinal STAT3 ameliorated the fully developed chronic itch. Mice with atopic dermatitis exhibited an increase in scratching elicited by intrathecal administration of the itch-inducer gastrin-releasing peptide (GRP), and this enhancement was normalized by suppressing STAT3-mediated reactive astrogliosis. Moreover, we identified lipocalin-2 (LCN2) as an astrocytic STAT3-dependent upregulated factor that was crucial for chronic itch, and we demonstrated that intrathecal administration of LCN2 to normal mice increased spinal GRP-evoked scratching. Our findings indicate that STAT3-dependent reactive astrocytes act as critical amplifiers of itching through a mechanism involving the enhancement of spinal itch signals by LCN2, thereby providing a previously unrecognized target for treating chronic itch..
8. Matsushita K et al., Chemokine (C-C motif) receptor 5 is an important pathological regulator in the development and maintenance of neuropathic pain., Anesthesiology, 120, 6, 1491-1503, 2014.06.
9. Masuda Takahiro et al., Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain., Nat Commun, 5, 3771, 2014.05, 神経のダメージで発症する慢性的な痛み(神経障害性疼痛)の原因タンパク質として「IRF5」を突き止めました。IRF5は、神経の損傷後に脳・脊髄の免疫細胞であるミクログリアで増え、IRF5欠損マウスでは痛みが弱くなっていました。さらに、2003年にP2X4受容体タンパク質のミクログリアでの増加が神経障害性疼痛に重要であることを英国科学誌Natureで発表していますが、今回見つかったIRF5がP2X4受容体を増やす実行役であることも明らかにしました。この研究成果は、慢性疼痛メカニズムの解明へ向けた大きな前進となり、痛みを緩和する治療薬の開発に応用できることが期待されます(Nature Communications誌掲載)。.
10. Masuda Takahiro, TSUDA MAKOTO, Ryohei Yoshinaga, Hidetoshi Saitoh, Keiko Ozato, Tomohiko Tamura, Kazuhide Inoue, IRF8 Is a Critical Transcription Factor for Transforming Microglia into a Reactive Phenotype, CELL REPORTS, 10.1016/j.celrep.2012.02.014, 1, 4, 334-340, 2012.04, 神経のダメージで発症する慢性的な激しい痛み(神経障害性疼痛)の原因タンパク質として「IRF8」を突き止めました。神経の損傷後,IRF8は脳・脊髄の免疫細胞と呼ばれる「ミクログリア」だけで劇的に増えており,同細胞の過度な活性化状態をつくりだして激しい痛みを引き起こすことを明らかにしました。また,IRF8は中枢神経においてミクログリア特異的に発現する転写因子として世界初の例であり,他の神経疾患においてもミクログリアの活性化が報告されていることから,他の領域にも本成果が波及することが期待できる。この研究成果は,慢性疼痛メカニズムの解明へ向けた大きな前進となり,痛みを緩和する治療薬の開発に応用できることが期待されます(Cell Reports誌掲載)。.
11. Biber K*, Tsuda M*, Tozaki-Saitoh H*, Tsukamoto K, Toyomitsu E, Masuda T, Boddeke H, Inoue K. (*equal contributors), Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development., EMBO J, 30, 9, 1864-1873, 2011.05.
12. Tsuda M, Kohro Y, Yano T, Tsujikawa T, Kitano J, Tozaki-Saitoh H, Koyanagi S, Ohdo S, Ji RR, Salter MW, Inoue K, JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats., Brain, 134, 4, 1127-1139, 2011.04.
13. Tsuda M, Toyomitsu E, Kometani M, Tozaki-Saitoh H, Inoue K, Mechanisms underlying fibronectin-induced up-regulation of P2X4R expression in microglia: distinct roles of PI3K-Akt and MEK-ERK signalling pathways, J Cell Mol Med, 13, 9b, 3251-9, 2009.09.
14. Tsuda M, Kuboyama K, Inoue T, Nagata K, Tozaki-Saitoh H, Inoue K, Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays, Mol Pain, 5, 28, 2009.06.
15. Tsuda M, Masuda T, Kitano J, Shimoyama H, Tozaki-Saitoh H, Inoue K, IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain, Proc Natl Acad Sci U S A, 106, 19, 8032-8037, 2009.05.
16. Shinozaki Y, Sumitomo K, Tsuda M, Koizumi S, Inoue K, Torimitsu K, Direct Observation of ATP-Induced Conformational Changes in Single P2X4 Receptors, PLoS Biol, 7, 5, e103, 2009.05.
17. Tozaki-Saitoh H, Tsuda M, Miyata H, Ueda K, Kohsaka S, Inoue K, P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury, J Neurosci 28: 4949-4956 (2008), 28: 4949-4956, 2008.05.
18. Tsuda M, Toyomitsu E, Komatsu T, Masuda T, Kunifusa E, Nasu-Tada K, Koizumi S, Yamamoto K, Ando J, Inoue K, Fibronectin/integrin system is involved in P2X(4) receptor upregulation in the spinal cord and neuropathic pain after nerve injury, Glia 56: 579-585 (2008), 2008.04.
19. Tsuda M, Ueno H, Kataoka A, Tozaki-Saitoh H, Inoue K, Activation of dorsal horn microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signaling, Glia 56: 378-386 (2008), 2008.03.
20. Lyn tyrosine kinase is required for P2X4 receptor upregulation and neuropathic pain after peripheral nerve injury, Tsuda M, Tozaki-Saitoh H, Masuda T, Toyomitsu E, Tezuka T, Yamamoto T, Inoue K, Glia 56: 50-58 (2008), 2008.01.
21. Tsuda M, Hasegawa S, Inoue K, P2X receptors-mediated cytosolic phospholipase A2 activation in primary afferent sensory neurons contributes to neuropathic pain, J Neurochem 103: 1408-1416 (2007), 2007.11.
22. Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M, Joshi BV, Jacobson KA, Kohsaka S, Inoue K., UDP acting at P2Y(6) receptors is a mediator of microglial phagocytosis., Nature. 446: 1091-1095 (2007), 2007.04.
23. Nasu-Tada K, Koizumi S, Tsuda M, Kunifusa E, Inoue K., Possible involvement of increase in spinal fibronectin following peripheral nerve injury in upregulation of microglial P2X4, a key molecule for mechanical allodynia., Glia. 2006 May;53(7):769-75., 2006.05.
24. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y., BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain., Nature. 2005 Dec 15;438(7070):1017-21. , 10.1038/nature04223, 438, 7070, 1017-1021, 2005.12.
25. Tsuda M, Mizokoshi A, Shigemoto-Mogami Y, Koizumi S, Inoue K., Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury., Glia. 2004 Jan 1;45(1):89-95., 10.1002/glia.10308, 45, 1, 89-95, 2004.01.
26. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K. Related Articles, Links , P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury., Nature. 2003 Aug 14;424(6950):778-83., 10.1038/nature01786, 424, 6950, 778-783, 2003.08.
27. Tsuda M, Koizumi S, Kita A, Shigemoto Y, Ueno S, Inoue K., Mechanical allodynia caused by intraplantar injection of P2X receptor agonist in rats: involvement of heteromeric P2X2/3 receptor signaling in capsaicin-insensitive primary afferent neurons., J Neurosci. 2000 Aug 1;20(15):RC90., 20, 15, 2000.08.
1. 津田誠, Role of spinal glial cells in the chronicity of pain, 第98回日本生理学会大会, 2021.03.
2. Makoto Tsuda, Modulation of mechanical sensitivity by spinal glial cells, 7th Asian pain symposium , 2017.10.
3. Makoto Tsuda, Glial cells: key elements for the pathogenesis of neuropathic pain, Asia Dry Eye Summit 2017, 2017.10.
4. Makoto Tsuda, Purinergic stimulation of spinal microglia contributes to chronic pain, XIII European Meeting on Glial Cells in Health and Disease, 2017.07.
5. Makoto Tsuda, Microglial modulation of neuropathic pain, Translational Pain Research Symposium, 2017.06.
6. TSUDA MAKOTO, Glial cells in the spinal cord and chronic pain, 19th Takeda Science Foundation Symposium on Bioscience, 2017.01.
7. TSUDA MAKOTO, Microglial purinergic signaling and neuropathic pain, 46th Annual Meeting Society for Neuroscience, 2016.11.
8. TSUDA MAKOTO, Spinal microglia activated by purinergic receptors and neuropathic pain, PSK-PSJ joint-symposium in 2016, 2016.10.
9. TSUDA MAKOTO, Spinal Microglia Activated by Purinergic Signaling and Neuropathic Pain, Keystone Symposia on Microglia in the Brain, 2016.06.
10. 津田 誠ら, 神経障害性疼痛におけるP2X4受容体陽性ミクログリアの役割, 日本薬学会第136年会, 2016.03.
11. 津田 誠, A crucial role of spinal astrocytes in chronic itch, 第89回日本薬理学会年会, 2016.03.
12. 津田 誠, Microglial purinergic signaling in the spinal cord and neuropathic pain, 6th Asian Pain Symposium, 2015.11.
13. 津田 誠, Dorsal horn astrocytes: new player in chronic itch, 8th World Congress on Itch (WCI 2015), 2015.09.
14. 津田 誠ら, Microglial transcription factors and neuropathic pain, 第58回日本神経化学会大会, 2015.09.
15. 津田 誠ら, Spinal glial cells and chronic pain, 2015 Cold Spring Harbor Asia Conference, 2015.06.
16. 津田 誠, Microglia as a pain maker in neuropathic pain: Rodent studies, 13th World Congress of Biological Psychiatry, 2015.06.
17. TSUDA MAKOTO et al., Microglial purinoceptors and chronic pain, Purines2014, 2014.07.
18. TSUDA MAKOTO et al., Non-cell-autonomous modulation of neuropathic pain by microglia, 17th World Congress of Basic and Clinical Pharmacology, 2014.07.
19. TSUDA MAKOTO, Purinergic signaling and chronic pain, Areces Foundation Symposium, 2014.03.
20. TSUDA MAKOTO, World First Discovery and Research-Neuropathic Pain, Neuralgia, 12th Asia Pacific Pharmaceutical Symposium, 2013.08.
21. Masuda Takahiro, TSUDA MAKOTO, Ryohei Yoshinaga, Hidetoshi Saitoh, Keiko Ozato, Tomohiko Tamura, Kazuhide Inoue, IRF8 is a critical transcription factor required for transforming microglia into a reactive phenotype after nerve injury, 42th Annual Meeting Society for Neuroscience, 2012.10.
22. TSUDA MAKOTO, Masuda Takahiro, Kazuhide Inoue, Spinal cord microglia in neuropathic pain signaling, 11th Biennial Meeting of Asian Pacific Society for Neurochemistry and 55th Meeting of Japanese Society for Neurochemistry, 2012.10.
23. Masuda Takahiro, TSUDA MAKOTO, Ryohei Yoshinaga, Tomohiko Tamura, Kazuhide Inoue, IRF5 is required for IRF8-derived microglial activation and contributes to neuropathic pain, 第55回日本神経化学会大会(APSN/JSN 2012), 2012.09.
24. 津田 誠, 井上 和秀, 活性化ミクログリアの転写制御と神経障害性疼痛, 第35回日本神経科学大会Neuro2012, 2012.09.
25. TSUDA MAKOTO, Masuda Takahiro, Ryohei Yoshinaga, Hidetoshi Saitoh, Keiko Ozato, Tomohiko Tamura, Kazuhide Inoue, IRF8 is a critical transcription for transforming microglia into a reactive phenotype, The 7th International Conference of Neurons and Brain Diseases, 2012.06.
26. Masuda Takahiro, TSUDA MAKOTO, Ryohei Yoshinaga, Nao Nishimoto, Shosuke Iwamoto, Hidetoshi Saitoh, Tomohiko Tamura, Kazuhide Inoue, IRF Family Transcription Factor Axis Governs Gene Expression Program in Microglia Gating Neuropathic Pain, Purine 2012, 2012.06.
27. TSUDA MAKOTO, Masuda Takahiro, Hidetoshi Saitoh, Kazuhide Inoue, Transcriptional regulation of P2X4R and neuropathic pain, Purine 2012, 2012.05.
28. Hidetoshi Saitoh, Emika Toyomitsu, TSUDA MAKOTO, 山下 智大, Yoshitaka Tanaka, Kazuhide Inoue, CCL2 promotes P2X4 receptor trafficking to the cell surface of microglia, Purine 2012, 2012.05.
  • IRF8 is a critical transcription for transforming microglia into a reactive phenotype