Skip to main content

Advertisement

SpringerLink
Log in

Modulation of Pain and Itch by Spinal Glia

  • Review
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Chronic pain and itch are a pathological operation of the somatosensory system at the levels of primary sensory neurons, spinal cord and brain. Pain and itch are clearly distinct sensations, and recent studies have revealed the separate neuronal pathways that are involved in each sensation. However, the mechanisms by which these sensations turn into a pathological chronic state are poorly understood. A proposed mechanism underlying chronic pain and itch involves abnormal excitability in dorsal horn neurons in the spinal cord. Furthermore, an increasing body of evidence from models of chronic pain and itch has indicated that synaptic hyperexcitability in the spinal dorsal horn might not be a consequence simply of changes in neurons, but rather of multiple alterations in glial cells. Thus, understanding the key roles of glial cells may provide us with exciting insights into the mechanisms of chronicity of pain and itch, and lead to new targets for treating chronic pain and itch.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Braz J, Solorzano C, Wang X, Basbaum AI. Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control. Neuron 2014, 82: 522–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. LaMotte RH, Dong X, Ringkamp M. Sensory neurons and circuits mediating itch. Nat Rev Neurosci 2014, 15: 19–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Han L, Dong X. Itch mechanisms and circuits. Ann Rev Biophys 2014, 43: 331–355.

    Article  CAS  Google Scholar 

  4. Somjen GG. Nervenkitt: notes on the history of the concept of neuroglia. Glia 1988, 1: 2–9.

    Article  CAS  PubMed  Google Scholar 

  5. Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 2005, 6: 626–640.

    Article  CAS  PubMed  Google Scholar 

  6. Freeman MR, Rowitch DH. Evolving concepts of gliogenesis: a look way back and ahead to the next 25 years. Neuron 2013, 80: 613–623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rowitch DH, Kriegstein AR. Developmental genetics of vertebrate glial-cell specification. Nature 2010, 468: 214–222.

    Article  CAS  PubMed  Google Scholar 

  8. Ginhoux F, Lim S, Hoeffel G, Low D, Huber T. Origin and differentiation of microglia. Front Cell Neurosci 2013, 7: 45.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ransohoff RM, Cardona AE. The myeloid cells of the central nervous system parenchyma. Nature 2010, 468: 253–262.

    Article  CAS  PubMed  Google Scholar 

  10. Eroglu C, Barres BA. Regulation of synaptic connectivity by glia. Nature 2010, 468: 223–231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Molofsky AV, Krencik R, Ullian EM, Tsai HH, Deneen B, Richardson WD, et al. Astrocytes and disease: a neurodevelopmental perspective. Genes Dev 2012, 26: 891–907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Khakh BS, Sofroniew MV. Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 2015, 18: 942–952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Freeman MR. Specification and morphogenesis of astrocytes. Science 2010, 330: 774–778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Perea G, Navarrete M, Araque A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 2009, 32: 421–431.

    Article  CAS  PubMed  Google Scholar 

  15. Halassa MM, Haydon PG. Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Ann Rev Physiol 2010, 72: 335–355.

    Article  CAS  Google Scholar 

  16. Bazargani N, Attwell D. Astrocyte calcium signaling: the third wave. Nat Neurosci 2016, 19: 182–189.

    Article  CAS  PubMed  Google Scholar 

  17. Clarke LE, Barres BA. Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci 2013, 14: 311–321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sofroniew MV. Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci 2015, 16: 249–263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Robel S, Sontheimer H. Glia as drivers of abnormal neuronal activity. Nat Neurosci 2016, 19: 28–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain 2013, 154 Suppl 1: S10–S28.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev 2011, 91: 461–553.

    Article  CAS  PubMed  Google Scholar 

  22. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010, 330: 841–845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci 2013, 16: 273–280.

    Article  CAS  PubMed  Google Scholar 

  24. Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 2014, 15: 300–312.

    Article  CAS  PubMed  Google Scholar 

  25. Crotti A, Ransohoff RM. Microglial physiology and pathophysiology: insights from genome-wide transcriptional profiling. Immunity 2016, 44: 505–515.

    Article  CAS  PubMed  Google Scholar 

  26. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 2005, 8: 752–758.

    Article  CAS  PubMed  Google Scholar 

  27. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005, 308: 1314–1318.

    Article  CAS  PubMed  Google Scholar 

  28. Davalos D, Akassoglou K. In vivo imaging of the mouse spinal cord using two-photon microscopy. J Vis Exp 2012: e2760.

  29. Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, et al. The P2Y(12) receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 2006, 9: 1512–1519.

    Article  CAS  PubMed  Google Scholar 

  30. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 2009, 29: 3974–3980.

    Article  CAS  PubMed  Google Scholar 

  31. Salter MW, Beggs S. Sublime microglia: expanding roles for the guardians of the CNS. Cell 2014, 158: 15–24.

    Article  CAS  PubMed  Google Scholar 

  32. Inoue K, Tsuda M. Microglia and neuropathic pain. Glia 2009, 57: 1469–1479.

    Article  PubMed  Google Scholar 

  33. Tsuda M, Beggs S, Salter MW, Inoue K. Microglia and intractable chronic pain. Glia 2013, 61: 55–61.

    Article  PubMed  Google Scholar 

  34. Gehrmann J, Banati RB. Microglial turnover in the injured CNS: activated microglia undergo delayed DNA fragmentation following peripheral nerve injury. J Neuropathol Exp Neurol 1995, 54: 680–688.

    Article  CAS  PubMed  Google Scholar 

  35. Tashima R, Mikuriya S, Tomiyama D, Shiratori-Hayashi M, Yamashita T, Kohro Y, et al. Bone marrow-derived cells in the population of spinal microglia after peripheral nerve injury. Sci Rep2016, 6: 23701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gu N, Peng J, Murugan M, Wang X, Eyo UB, Sun D, et al. Spinal microgliosis due to resident microglial proliferation is required for pain hypersensitivity after peripheral nerve injury. Cell Rep 2016, 16: 605–614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tsuda M, Inoue K, Salter MW. Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia. Trends Neurosci 2005, 28: 101–107.

    Article  CAS  PubMed  Google Scholar 

  38. 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 2009, 106: 8032–8037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Guan Z, Kuhn JA, Wang X, Colquitt B, Solorzano C, Vaman S, et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat Neurosci 2016, 19: 94–101.

    Article  CAS  PubMed  Google Scholar 

  40. Okubo M, Yamanaka H, Kobayashi K, Dai Y, Kanda H, Yagi H, et al. Macrophage-colony stimulating factor derived from injured primary afferent induces proliferation of spinal microglia and neuropathic pain in rats. PLoS One 2016, 11: e0153375.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Zhang J, Shi XQ, Echeverry S, Mogil JS, De Koninck Y, Rivest S. Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neurosci 2007, 27: 12396–12406.

    Article  CAS  PubMed  Google Scholar 

  42. Padi SS, Shi XQ, Zhao YQ, Ruff MR, Baichoo N, Pert CB, et al. Attenuation of rodent neuropathic pain by an orally active peptide, RAP-103, which potently blocks CCR2- and CCR5-mediated monocyte chemotaxis and inflammation. Pain 2012, 153: 95–106.

    Article  CAS  PubMed  Google Scholar 

  43. Echeverry S, Shi XQ, Rivest S, Zhang J. Peripheral nerve injury alters blood-spinal cord barrier functional and molecular integrity through a selective inflammatory pathway. J Neurosci 2011, 31: 10819–10828.

    Article  CAS  PubMed  Google Scholar 

  44. Isami K, Haraguchi K, So K, Asakura K, Shirakawa H, Mori Y, et al. Involvement of TRPM2 in peripheral nerve injury-induced infiltration of peripheral immune cells into the spinal cord in mouse neuropathic pain model. PLoS One 2013, 8: e66410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 2003, 424: 778–783.

    Article  CAS  PubMed  Google Scholar 

  46. McCleskey EW. Neurobiology: new player in pain. Nature 2003, 424: 729–730.

    Article  CAS  PubMed  Google Scholar 

  47. 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 2009, 7: e103.

    Article  CAS  Google Scholar 

  48. Kawate T, Michel JC, Birdsong WT, Gouaux E. Crystal structure of the ATP-gated P2X(4) ion channel in the closed state. Nature 2009, 460: 592–598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ralevic V, Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev 1998, 50: 413–492.

    CAS  PubMed  Google Scholar 

  50. Khakh BS, Burnstock G, Kennedy C, King BF, North RA, Seguela P, et al. International union of pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits. Pharmacol Rev 2001, 53: 107–118.

    CAS  PubMed  Google Scholar 

  51. North RA. Molecular physiology of P2X receptors. Physiol Rev 2002, 82: 1013–1067.

    Article  CAS  PubMed  Google Scholar 

  52. Ulmann L, Hatcher JP, Hughes JP, Chaumont S, Green PJ, Conquet F, et al. Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J Neurosci 2008, 28: 11263–11268.

    Article  CAS  PubMed  Google Scholar 

  53. 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 2009, 5: 28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Zhang Z, Zhang ZY, Fauser U, Schluesener HJ. Mechanical allodynia and spinal up-regulation of P2X4 receptor in experimental autoimmune neuritis rats. Neuroscience 2008, 152: 495–501.

    Article  CAS  PubMed  Google Scholar 

  55. Matsumura Y, Yamashita T, Sasaki A, Nakata E, Kohno K, Masuda T, et al. A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain. Sci Rep 2016, 6: 32461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sorge RE, Mapplebeck JC, Rosen S, Beggs S, Taves S, Alexander JK, et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci 2015, 18: 1081–1083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sorge RE, LaCroix-Fralish ML, Tuttle AH, Sotocinal SG, Austin JS, Ritchie J, et al. Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. J Neurosci 2011, 31: 15450–15454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Taves S, Berta T, Liu DL, Gan S, Chen G, Kim YH, et al. Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord. Brain Behav Immun 2016, 55: 70–81.

    Article  CAS  PubMed  Google Scholar 

  59. Tanga FY, Nutile-McMenemy N, DeLeo JA. The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc Natl Acad Sci U S A 2005, 102: 5856–5861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Jin SX, Zhuang ZY, Woolf CJ, Ji RR. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci 2003, 23: 4017–4022.

    CAS  PubMed  Google Scholar 

  61. 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, 45: 89–95.

    Article  PubMed  Google Scholar 

  62. Tamura T, Yanai H, Savitsky D, Taniguchi T. The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol 2008, 26: 535–584.

    Article  CAS  PubMed  Google Scholar 

  63. Masuda T, Tsuda M, Yoshinaga R, Tozaki-Saitoh H, Ozato K, Tamura T, et al. IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype. Cell Rep 2012, 1: 334–340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kurotaki D, Osato N, Nishiyama A, Yamamoto M, Ban T, Sato H, et al. Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation. Blood 2013, 121: 1839–1849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Masuda T, Iwamoto S, Yoshinaga R, Tozaki-Saitoh H, Nishiyama A, Mak TW, et al. Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain. Nat Commun 2014, 5: 3771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sawynok J, Downie JW, Reid AR, Cahill CM, White TD. ATP release from dorsal spinal cord synaptosomes: characterization and neuronal origin. Brain Res 1993, 610: 32–38.

    Article  CAS  PubMed  Google Scholar 

  67. Li P, Calejesan AA, Zhuo M. ATP P2x receptors and sensory synaptic transmission between primary afferent fibers and spinal dorsal horn neurons in rats. J Neurophysiol 1998, 80: 3356–3360.

    Article  CAS  PubMed  Google Scholar 

  68. Nakatsuka T, Gu JG. ATP P2X receptor-mediated enhancement of glutamate release and evoked EPSCs in dorsal horn neurons of the rat spinal cord. J Neurosci 2001, 21: 6522–6531.

    CAS  PubMed  Google Scholar 

  69. Bardoni R, Goldstein PA, Lee CJ, Gu JG, MacDermott AB. ATP P2X receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord. J Neurosci 1997, 17: 5297–5304.

    CAS  PubMed  Google Scholar 

  70. Jo YH, Schlichter R. Synaptic corelease of ATP and GABA in cultured spinal neurons. Nat Neurosci 1999, 2: 241–245.

    Article  CAS  PubMed  Google Scholar 

  71. Fam SR, Gallagher CJ, Salter MW. P2Y(1) purinoceptor-mediated Ca(2+) signaling and Ca(2+) wave propagation in dorsal spinal cord astrocytes. J Neurosci 2000, 20: 2800–2808.

    CAS  PubMed  Google Scholar 

  72. Sawada K, Echigo N, Juge N, Miyaji T, Otsuka M, Omote H, et al. Identification of a vesicular nucleotide transporter. Proc Natl Acad Sci U S A 2008, 105: 5683–5686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Masuda T, Ozono Y, Mikuriya S, Kohro Y, Tozaki-Saitoh H, Iwatsuki K, et al. Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain. Nat Commun 2016, 7: 12529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Trang T, Beggs S, Wan X, Salter MW. P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J Neurosci 2009, 29: 3518–3528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005, 438: 1017–1021.

    Article  CAS  PubMed  Google Scholar 

  76. Hildebrand ME, Xu J, Dedek A, Li Y, Sengar AS, Beggs S, et al. Potentiation of synaptic GluN2B NMDAR currents by Fyn kinase is gated through BDNF-mediated disinhibition in spinal pain processing. Cell Rep 2016, 17: 2753–2765.

    Article  CAS  PubMed  Google Scholar 

  77. Ikeda H, Tsuda M, Inoue K, Murase K. Long-term potentiation of neuronal excitation by neuron-glia interactions in the rat spinal dorsal horn. Eur J Neurosci 2007, 25: 1297–1306.

    Article  PubMed  Google Scholar 

  78. Kawasaki Y, Zhang L, Cheng JK, Ji RR. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci 2008, 28: 5189–5194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ikoma A, Steinhoff M, Stander S, Yosipovitch G, Schmelz M. The neurobiology of itch. Nat Rev Neurosci 2006, 7: 535–547.

    Article  CAS  PubMed  Google Scholar 

  80. Ikoma A. Updated neurophysiology of itch. Biol Pharm Bull 2013, 36: 1235–1240.

    Article  CAS  PubMed  Google Scholar 

  81. Dhand A, Aminoff MJ. The neurology of itch. Brain 2014, 137: 313–322.

    Article  PubMed  Google Scholar 

  82. Yosipovitch G, Bernhard JD. Clinical practice. Chronic pruritus. N Engl J Med 2013, 368: 1625–1634.

    Article  CAS  PubMed  Google Scholar 

  83. Miller G. Biomedicine. Grasping for clues to the biology of itch. Science 2007, 318: 188–189.

    Article  Google Scholar 

  84. Tanaka A, Amagai Y, Oida K, Matsuda H. Recent findings in mouse models for human atopic dermatitis. Exp Anim 2012, 61: 77–84.

    Article  PubMed  Google Scholar 

  85. Bautista DM, Wilson SR, Hoon MA. Why we scratch an itch: the molecules, cells and circuits of itch. Nat Neurosci 2014, 17: 175–182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kuraishi Y. Methods for preclinical assessment of antipruritic agents and itch mechanisms independent of mast-cell histamine. Biol Pharm Bull 2015, 38: 635–644.

    Article  CAS  PubMed  Google Scholar 

  87. Shiratori-Hayashi M, Koga K, Tozaki-Saitoh H, Kohro Y, Toyonaga H, Yamaguchi C, et al. STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch. Nat Med 2015, 21: 927–931.

    Article  CAS  PubMed  Google Scholar 

  88. Sofroniew MV. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 2009, 32: 638–647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Liu T, Han Q, Chen G, Huang Y, Zhao LX, Berta T, et al. Toll-like receptor 4 contributes to chronic itch, alloknesis, and spinal astrocyte activation in male mice. Pain 2016, 157: 806–817.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Tominaga M, Ogawa H, Takamori K. Histological characterization of cutaneous nerve fibers containing gastrin-releasing peptide in NC/Nga mice: an atopic dermatitis model. J Invest Dermatol 2009, 129: 2901–2905.

    Article  CAS  PubMed  Google Scholar 

  91. Tominaga M, Tengara S, Kamo A, Ogawa H, Takamori K. Psoralen-ultraviolet A therapy alters epidermal Sema3A and NGF levels and modulates epidermal innervation in atopic dermatitis. J Dermatol Sci 2009, 55: 40–46.

    Article  CAS  PubMed  Google Scholar 

  92. Tominaga M, Takamori K. Itch and nerve fibers with special reference to atopic dermatitis: therapeutic implications. J Dermatol 2014, 41: 205–212.

    Article  CAS  PubMed  Google Scholar 

  93. Sun YG, Chen ZF. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 2007, 448: 700–703.

    Article  CAS  PubMed  Google Scholar 

  94. Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF. Cellular basis of itch sensation. Science 2009, 325: 1531–1534.

    Article  CAS  PubMed  Google Scholar 

  95. Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, et al. Genomic analysis of reactive astrogliosis. J Neurosci 2012, 32: 6391–6410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Berard JL, Zarruk JG, Arbour N, Prat A, Yong VW, Jacques FH, et al. Lipocalin 2 is a novel immune mediator of experimental autoimmune encephalomyelitis pathogenesis and is modulated in multiple sclerosis. Glia 2012, 60: 1145–1159.

    Article  PubMed  Google Scholar 

  97. Bi F, Huang C, Tong J, Qiu G, Huang B, Wu Q, et al. Reactive astrocytes secrete lcn2 to promote neuron death. Proc Natl Acad Sci U S A 2013, 110: 4069–4074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mucha M, Skrzypiec AE, Schiavon E, Attwood BK, Kucerova E, Pawlak R. Lipocalin-2 controls neuronal excitability and anxiety by regulating dendritic spine formation and maturation. Proc Natl Acad Sci U S A 2011, 108: 18436–18441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhuang ZY, Gerner P, Woolf CJ, Ji RR. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 2005, 114: 149–159.

    Article  PubMed  Google Scholar 

  100. Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, et al. A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 2006, 26: 3551–3560.

    Article  CAS  PubMed  Google Scholar 

  101. Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Decosterd I. Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. Neuron Glia Biol 2006, 2: 259–269.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Tsuda M, Kohro Y, Yano T, Tsujikawa T, Kitano J, Tozaki-Saitoh H, et al. JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain 2011, 134: 1127–1139.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Tsujino H, Kondo E, Fukuoka T, Dai Y, Tokunaga A, Miki K, et al. Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury. Mol Cell Neurosci 2000, 15: 170–182.

    Article  CAS  PubMed  Google Scholar 

  104. Tsuda M, Inoue K. Neuron-microglia interaction by purinergic signaling in neuropathic pain following neurodegeneration. Neuropharmacology 2016, 104: 76–81.

    Article  CAS  PubMed  Google Scholar 

  105. Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, et al. CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 2001, 4: 702–710.

    Article  CAS  PubMed  Google Scholar 

  106. Pascual O, Ben Achour S, Rostaing P, Triller A, Bessis A. Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci U S A 2012, 109: E197–E205.

    Article  CAS  PubMed  Google Scholar 

  107. Liu W, Tang Y, Feng J. Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system. Life Sci 2011, 89: 141–146.

    Article  CAS  PubMed  Google Scholar 

  108. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017, 541: 481–487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

MT is supported by JSPS KAKENHI Grant Numbers 15H02522, the Core Research for Evolutional Science and Technology (CREST) program and the Practical Research Project for Allergic Diseases and Immunology (Research on Allergic Diseases and Immunology) from Japan Agency for Medical Research and Development, the Toray Science Foundation, Takeda Science Foundation, and The Nakatomi Foundation.

Author information

Authors and Affiliations

  1. Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

    Makoto Tsuda

  2. Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

    Makoto Tsuda

Authors
  1. Makoto Tsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Makoto Tsuda.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tsuda, M. Modulation of Pain and Itch by Spinal Glia. Neurosci. Bull. 34, 178–185 (2018). https://doi.org/10.1007/s12264-017-0129-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-017-0129-y

Keywords

Search

Navigation