SpringerLink
Log in

Microglia in the CNS and Neuropathic Pain

  • Chapter
  • First Online:
Advances in Pain Research: Mechanisms and Modulation of Chronic Pain

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1099))

Abstract

Neuropathic pain occurring after peripheral nerve injury is not simply a consequence of temporal continuity of acute nociceptive signals, but rather of maladaptive nervous system function. Over the past decades, a body of literature has provided evidence for the necessity and sufficiency of microglia, the tissue-resident macrophages of the central nervous system, for nerve injury-induced alterations in synaptic function. Recent studies have also revealed active roles for microglia in brain regions important for emotion and memory. In this chapter, I highlight recent advances in our understanding of the mechanisms that underlie the role of spinal and brain microglia in neuropathic pain, with a focus on how microglia are activated and alter synaptic function. I also discuss the therapeutic potential of microglia from recent advances in the development of new drugs targeting microglia, which may facilitate translation from the bench to bedside.

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

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
EUR 29.95
Price includes VAT (Thailand)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
EUR 96.29
Price includes VAT (Thailand)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
EUR 114.99
Price excludes VAT (Thailand)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info
Hardcover Book
EUR 159.99
Price excludes VAT (Thailand)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM (2011) Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 14:1142–1149

    Article  CAS  PubMed  Google Scholar 

  2. Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10:1538–1543

    Article  CAS  PubMed  Google Scholar 

  3. Biber K, Tsuda M, Tozaki-Saitoh H, Tsukamoto K, Toyomitsu E, Masuda T et al (2011) Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. EMBO J 30:1864–1873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bliss TV, Collingridge GL, Kaang BK, Zhuo M (2016) Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain. Nat Rev Neurosci 17:485–496

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Burma NE, Bonin RP, Leduc-Pessah H, Baimel C, Cairncross ZF, Mousseau M et al (2017) Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents. Nat Med 23:355–360

    Article  CAS  PubMed  Google Scholar 

  7. Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G et al (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–143

    Article  CAS  PubMed  Google Scholar 

  8. Calvo M, Zhu N, Tsantoulas C, Ma Z, Grist J, Loeb JA et al (2010) Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury. J Neurosci 30:5437–5450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen G, Park CK, **e RG, Berta T, Nedergaard M, Ji RR (2014) Connexin-43 induces chemokine release from spinal cord astrocytes to maintain late-phase neuropathic pain in mice. Brain 137:2193–2209

    Article  PubMed  PubMed Central  Google Scholar 

  10. Chessell IP, Hatcher JP, Bountra C, Michel AD, Hughes JP, Green P et al (2005) Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114:386–396

    Article  CAS  PubMed  Google Scholar 

  11. Clark AK, Gruber-Schoffnegger D, Drdla-Schutting R, Gerhold KJ, Malcangio M, Sandkuhler J (2015) Selective activation of microglia facilitates synaptic strength. J Neurosci 35:4552–4570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Clark AK, Malcangio M (2014) Fractalkine/CX3CR1 signaling during neuropathic pain. Front Cell Neurosci 8:121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Clark AK, Staniland AA, Marchand F, Kaan TK, McMahon SB, Malcangio M (2010) P2X7-dependent release of interleukin-1beta and nociception in the spinal cord following lipopolysaccharide. J Neurosci 30:573–582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Clark AK, Yip PK, Grist J, Gentry C, Staniland AA, Marchand F et al (2007) Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc Natl Acad Sci U S A 104:10655–10660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Corder G, Tawfik VL, Wang D, Sypek EI, Low SA, Dickinson JR et al (2017) Loss of mu opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia. Nat Med 23:164–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Davalos D, Akassoglou K (2012) In vivo imaging of the mouse spinal cord using two-photon microscopy. J Vis Exp 59:e2760

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. Del Rio-Hortega P (1919) El tercer elemento de los centros nerviosos I La microglia en estado normal II Intervencíon de la microglia en los procesos patológicos III Naturaleza probable de la microglia. Bol Soc Biol 9:69–120

    Google Scholar 

  20. Di Virgilio F, Dal Ben D, Sarti AC, Giuliani AL, Falzoni S (2017) The P2X7 receptor in infection and inflammation. Immunity 47:15–31

    Article  CAS  PubMed  Google Scholar 

  21. Elmore MR, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA et al (2014) Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82:380–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ferrini F, Trang T, Mattioli TA, Laffray S, Del’Guidice T, Lorenzo LE et al (2013) Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl(-) homeostasis. Nat Neurosci 16:183–192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ et al (2009) JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci 29:4096–4108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S et al (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13:1118–1128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Gilmore SA (1975) Proliferation of non-neuronal cells in spinal cords of irradiated, immature rats following transection of the sciatic nerve. Anat Rec 181:799–811

    Article  CAS  PubMed  Google Scholar 

  28. Gilmore SA, Skinner RD (1979) Intraspinal non-neuronal cellular responses to peripheral nerve injury. Anat Rec 194:369–387

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L et al (2015) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518:547–551

    Article  CAS  PubMed  Google Scholar 

  31. Gosselin D, Link VM, Romanoski CE, Fonseca GJ, Eichenfield DZ, Spann NJ et al (2014) Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159:1327–1340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Heneka MT, Kummer MP, Latz E (2014) Innate immune activation in neurodegenerative disease. Nat Rev Immunol 14:463–477

    Article  CAS  PubMed  Google Scholar 

  36. Hewitt E, Pitcher T, Rizoska B, Tunblad K, Henderson I, Sahlberg BL et al (2016) Selective Cathepsin S inhibition with MIV-247 attenuates mechanical allodynia and enhances the antiallodynic effects of gabapentin and pregabalin in a mouse model of neuropathic pain. J Pharmacol Exp Ther 358:387–396

    Article  CAS  PubMed  Google Scholar 

  37. Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK et al (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16:1896–1905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  39. Horvath RJ, Romero-Sandoval EA, De Leo JA (2010) Inhibition of microglial P2X4 receptors attenuates morphine tolerance, Iba1, GFAP and mu opioid receptor protein expression while enhancing perivascular microglial ED2. Pain 150:401–413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hutchinson MR, Shavit Y, Grace PM, Rice KC, Maier SF, Watkins LR (2011) Exploring the neuroimmunopharmacology of opioids: an integrative review of mechanisms of central immune signaling and their implications for opioid analgesia. Pharmacol Rev 63:772–810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Imura Y, Morizawa Y, Komatsu R, Shibata K, Shinozaki Y, Kasai H et al (2013) Microglia release ATP by exocytosis. Glia 61:1320–1330

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  43. Inoue K, Tsuda M (2018) Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci 19:138–152

    Article  CAS  PubMed  Google Scholar 

  44. Jacobson KA, Muller CE (2016) Medicinal chemistry of adenosine, P2Y and P2X receptors. Neuropharmacology 104:31–49

    Article  CAS  PubMed  Google Scholar 

  45. Ji RR, Xu ZZ, Gao YJ (2014) Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov 13:533–548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. ** SX, Zhuang ZY, Woolf CJ, Ji RR (2003) 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 23:4017–4022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  48. Kanda H, Kobayashi K, Yamanaka H, Okubo M, Noguchi K (2017) Microglial TNFalpha induces COX2 and PGI2 synthase expression in spinal endothelial cells during neuropathic pain. eNeuro 4. https://doi.org/10.1523/ENEURO.0064-17.2017

    Article  PubMed  PubMed Central  Google Scholar 

  49. Kato Y, Hiasa M, Ichikawa R, Hasuzawa N, Kadowaki A, Iwatsuki K et al (2017) Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain. Proc Natl Acad Sci U S A 114:E6297–E6305

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  53. Kim D, Kim MA, Cho IH, Kim MS, Lee S, Jo EK et al (2007) A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J Biol Chem 282:14975–14983

    Article  CAS  PubMed  Google Scholar 

  54. Kobayashi K, Takahashi E, Miyagawa Y, Yamanaka H, Noguchi K (2011) Induction of the P2X7 receptor in spinal microglia in a neuropathic pain model. Neurosci Lett 504:57–61

    Article  CAS  PubMed  Google Scholar 

  55. Kobayashi M, Konishi H, Sayo A, Takai T, Kiyama H (2016) TREM2/DAP12 signal elicits proinflammatory response in microglia and exacerbates neuropathic pain. J Neurosci 36:11138–11150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kohro Y, Sakaguchi E, Tashima R, Tozaki-Saitoh H, Okano H, Inoue K et al (2015) A new minimally-invasive method for microinjection into the mouse spinal dorsal horn. Sci Rep 5:14306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kronschlager MT, Drdla-Schutting R, Gassner M, Honsek SD, Teuchmann HL, Sandkuhler J (2016) Gliogenic LTP spreads widely in nociceptive pathways. Science 354:1144–1148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kuner R, Flor H (2016) Structural plasticity and reorganisation in chronic pain. Nat Rev Neurosci 18:20–30

    Article  CAS  PubMed  Google Scholar 

  59. Larochelle A, Bellavance MA, Michaud JP, Rivest S (2015) Bone marrow-derived macrophages and the CNS: an update on the use of experimental chimeric mouse models and bone marrow transplantation in neurological disorders. Biochim Biophys Acta 1862:310–322

    Article  CAS  PubMed  Google Scholar 

  60. Leduc-Pessah H, Weilinger NL, Fan CY, Burma NE, Thompson RJ, Trang T (2017) Site-specific regulation of P2X7 receptor function in microglia gates morphine analgesic tolerance. J Neurosci 37:10154–10172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lim H, Lee H, Noh K, Lee SJ (2017) IKK/NF-kappaB-dependent satellite glia activation induces spinal cord microglia activation and neuropathic pain after nerve injury. Pain 158:1666–1677

    Article  CAS  PubMed  Google Scholar 

  62. Liu Y, Zhou LJ, Wang J, Li D, Ren WJ, Peng J et al (2017) TNF-alpha differentially regulates synaptic plasticity in the hippocampus and spinal cord by microglia-dependent mechanisms after peripheral nerve injury. J Neurosci 37:871–881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Masuda T, Iwamoto S, Mikuriya S, Tozaki-Saitoh H, Tamura T, Tsuda M et al (2015) Transcription factor IRF1 is responsible for IRF8-mediated IL-1beta expression in reactive microglia. J Pharmacol Sci 128:216–220

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Miyamoto K, Kume K, Ohsawa M (2017) Role of microglia in mechanical allodynia in the anterior cingulate cortex. J Pharmacol Sci 134:158–165

    Article  CAS  PubMed  Google Scholar 

  69. Miyoshi K, Obata K, Kondo T, Okamura H, Noguchi K (2008) Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. J Neurosci 28:12775–12787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Muffat J, Li Y, Yuan B, Mitalipova M, Omer A, Corcoran S et al (2016) Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med 22:1358–1367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ni HD, Yao M, Huang B, Xu LS, Zheng Y, Chu YX et al (2016) Glial activation in the periaqueductal gray promotes descending facilitation of neuropathic pain through the p38 MAPK signaling pathway. J Neurosci Res 94:50–61

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  74. Ohgidani M, Kato TA, Hosoi M, Tsuda M, Hayakawa K, Hayaki C et al (2017) Fibromyalgia and microglial TNF-alpha: translational research using human blood induced microglia-like cells. Sci Rep 7:11882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ohgidani M, Kato TA, Setoyama D, Sagata N, Hashimoto R, Shigenobu K et al (2014) Direct induction of ramified microglia-like cells from human monocytes: dynamic microglial dysfunction in Nasu-Hakola disease. Sci Rep 4:4957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Oida H, Namba T, Sugimoto Y, Ushikubi F, Ohishi H, Ichikawa A et al (1995) In situ hybridization studies of prostacyclin receptor mRNA expression in various mouse organs. Br J Pharmacol 116:2828–2837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Park CK, Lu N, Xu ZZ, Liu T, Serhan CN, Ji RR (2011) Resolving TRPV1- and TNF-alpha-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J Neurosci 31:15072–15085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Peirs C, Seal RP (2016) Neural circuits for pain: recent advances and current views. Science 354:578–584

    Article  CAS  PubMed  Google Scholar 

  80. Reeve AJ, Patel S, Fox A, Walker K, Urban L (2000) Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat. Eur J Pain 4:247–257

    Article  CAS  PubMed  Google Scholar 

  81. Sawada A, Niiyama Y, Ataka K, Nagaishi K, Yamakage M, Fujimiya M (2014) Suppression of bone marrow-derived microglia in the amygdala improves anxiety-like behavior induced by chronic partial sciatic nerve ligation in mice. Pain 155:1762–1772

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K et al (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336:86–90

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tashima R, Mikuriya S, Tomiyama D, Shiratori-Hayashi M, Yamashita T, Kohro Y et al (2016) Bone marrow-derived cells in the population of spinal microglia after peripheral nerve injury. Sci Rep 6:23701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Tay TL, Mai D, Dautzenberg J, Fernandez-Klett F, Lin G, Sagar et al (2017) A new fate map** system reveals context-dependent random or clonal expansion of microglia. Nat Neurosci 20:793–803

    Article  CAS  PubMed  Google Scholar 

  89. Taylor AM, Castonguay A, Taylor AJ, Murphy NP, Ghogha A, Cook C et al (2015) Microglia disrupt mesolimbic reward circuitry in chronic pain. J Neurosci 35:8442–8450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Taylor AM, Mehrabani S, Liu S, Taylor AJ, Cahill CM (2017) Topography of microglial activation in sensory- and affect-related brain regions in chronic pain. J Neurosci Res 95:1330–1335

    Article  CAS  PubMed  Google Scholar 

  91. Trang T, Beggs S, Wan X, Salter MW (2009) 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 29:3518–3528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  94. Tsuda M, Kuboyama K, Inoue T, Nagata K, Tozaki-Saitoh H, Inoue K (2009a) Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays. Mol Pain 5:28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Tsuda M, Masuda T, Kitano J, Shimoyama H, Tozaki-Saitoh H, Inoue K (2009b) IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc Natl Acad Sci U S A 106:8032–8037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Tsuda M, Masuda T, Tozaki-Saitoh H, Inoue K (2013) P2X4 receptors and neuropathic pain. Front Cell Neurosci 7:191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  98. Tsuda M, Toyomitsu E, Komatsu T, Masuda T, Kunifusa E, Nasu-Tada K et al (2008a) Fibronectin/integrin system is involved in P2X(4) receptor upregulation in the spinal cord and neuropathic pain after nerve injury. Glia 56:579–585

    Article  PubMed  Google Scholar 

  99. Tsuda M, Tozaki-Saitoh H, Masuda T, Toyomitsu E, Tezuka T, Yamamoto T et al (2008b) Lyn tyrosine kinase is required for P2X(4) receptor upregulation and neuropathic pain after peripheral nerve injury. Glia 56:50–58

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T et al (2003) Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 23:8692–8700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wake H, Moorhouse AJ, Miyamoto A, Nabekura J (2013) Microglia: actively surveying and sha** neuronal circuit structure and function. Trends Neurosci 36:209–217

    Article  CAS  PubMed  Google Scholar 

  103. Wang Y, Szretter KJ, Vermi W, Gilfillan S, Rossini C, Cella M et al (2012) IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol 13:753–760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wang Z, Ma W, Chabot JG, Quirion R (2009) Cell-type specific activation of p38 and ERK mediates calcitonin gene-related peptide involvement in tolerance to morphine-induced analgesia. FASEB J 23:2576–2586

    Article  CAS  PubMed  Google Scholar 

  105. Woolf CJ, Salter MW (2000) Neuronal plasticity: increasing the gain in pain. Science 288:1765–1769

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhao J, Seereeram A, Nassar MA, Levato A, Pezet S, Hathaway G et al (2006) Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain. Mol Cell Neurosci 31:539–548

    Article  CAS  PubMed  Google Scholar 

  108. Zhou D, Chen ML, Zhang YQ, Zhao ZQ (2010) Involvement of spinal microglial P2X7 receptor in generation of tolerance to morphine analgesia in rats. J Neurosci 30:8042–8047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhuang ZY, Kawasaki Y, Tan PH, Wen YR, Huang J, Ji RR (2007) Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain Behav Immun 21:642–651

    Article  CAS  PubMed  Google Scholar 

  110. Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR et al (2006) 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 26:3551–3560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by JSPS KAKENHI Grant Numbers JP15H02522, by the Core Research for Evolutional Science and Technology (CREST) program from Japan Agency for Medical Research and Development (AMED), by the Practical Research Project for Allergic Diseases and Immunology (Research on Allergic Diseases and Immunology) from AMED, by Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under Grant Number JP18am0101091, and by the Toray Science Foundation.

Author information

Authors and Affiliations

  1. Department of Life Innovation, 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 .

Editor information

Editors and Affiliations

  1. Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    Bai-Chuang Shyu

  2. Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), Okazaki, Aichi, Japan

    Makoto Tominaga

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Tsuda, M. (2018). Microglia in the CNS and Neuropathic Pain. In: Shyu, BC., Tominaga, M. (eds) Advances in Pain Research: Mechanisms and Modulation of Chronic Pain. Advances in Experimental Medicine and Biology, vol 1099. Springer, Singapore. https://doi.org/10.1007/978-981-13-1756-9_7

Download citation

Publish with us

Policies and ethics

Search

Navigation