Advertisement

Neurotherapeutics

, Volume 7, Issue 4, pp 482–493 | Cite as

Targeting astrocyte signaling for chronic pain

  • Yong-Jing GaoEmail author
  • Ru-Rong JiEmail author
Review Article

Summary

Clinical management of chronic pain after nerve injury (neuropathic pain) and tumor invasion (cancer pain) is a real challenge due to our limited understanding of the cellular mechanisms that initiate and maintain chronic pain. It has been increasingly recognized that glial cells, such as microglia and astrocytes in the CNS play an important role in the development and maintenance of chronic pain. Notably, astrocytes make very close contacts with synapses and astrocyte reaction after nerve injury, arthritis, and tumor growth is more persistent than microglial reaction, and displays a better correlation with chronic pain behaviors. Accumulating evidence indicates that activated astrocytes can release proinflammatory cytokines (e.g., interleukin [IL]-1β) and chemokines (e.g., monocyte chemoattractant protein-1 [MCP-1]/also called CCL2) in the spinal cord to enhance and prolong persistent pain states. IL-1β can powerfully modulate synaptic transmission in the spinal cord by enhancing excitatory synaptic transmission and suppressing inhibitory synaptic transmission. IL-1β activation (cleavage) in the spinal cord after nerve injury requires the matrix metalloprotease-2. In particular, nerve injury and inflammation activate the c-Jun N-terminal kinase in spinal astrocytes, leading to a substantial increase in the expression and release of MCP-1. The MCP-1 increases pain sensitivity via direct activation of NMDA receptors in dorsal horn neurons. Pharmacological inhibition of the IL-1β, c-Jun N-terminal kinase, MCP-1, or matrix metalloprotease-2 signaling via spinal administration has been shown to attenuate inflammatory, neuropathic, or cancer pain. Therefore, interventions in specific signaling pathways in astrocytes may offer new approaches for the management of chronic pain.

Key Words

Neuropathic pain nerve injury spinal cord cytokine chemokine MAP kinase glia 

References

  1. 1.
    Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001;413: 203–210.PubMedCrossRefGoogle Scholar
  2. 2.
    Lundeberg T, Ekholm J. Pain-from periphery to brain. Disabil Rehabil 2002;24: 402–406.PubMedCrossRefGoogle Scholar
  3. 3.
    Millan MJ. Descending control of pain. Prog Neurobiol 2002;66: 355–474.PubMedCrossRefGoogle Scholar
  4. 4.
    Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999;353: 1959–1964.PubMedCrossRefGoogle Scholar
  5. 5.
    Dubner R, Ruda MA. Activity-dependent neuronal plasticity following tissue injury and inflammation. Trends Neurosci 1992;15: 96–103.PubMedCrossRefGoogle Scholar
  6. 6.
    Mantyh PW, Clohisy DR, Koltzenburg M, Hunt SP. Molecular mechanisms of cancer pain. Nat Rev Cancer 2002;2: 201–209.PubMedCrossRefGoogle Scholar
  7. 7.
    Willis CL, Davis TP. Chronic inflammatory pain and the neurovascular unit: a central role for glia in maintaining BBB integrity? Curr Pharm Des 2008;14: 1625–1643.PubMedCrossRefGoogle Scholar
  8. 8.
    Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009;32: 1–32.PubMedCrossRefGoogle Scholar
  9. 9.
    Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci 2003;26: 696–705.PubMedCrossRefGoogle Scholar
  10. 10.
    Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell 2009;139: 267–284.PubMedCrossRefGoogle Scholar
  11. 11.
    Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60: 1524–1534.PubMedCrossRefGoogle Scholar
  12. 12.
    Ho KY, Siau C. Chronic pain management: therapy, drugs and needles. Ann Acad Med Singapore 2009;38: 929–930.PubMedGoogle Scholar
  13. 13.
    Moalem G, Tracey DJ. Immune and inflammatory mechanisms in neuropathic pain. Brain Res Rev 2006;51: 240–264.PubMedCrossRefGoogle Scholar
  14. 14.
    Aldskogius H, Kozlova EN. Central neuron-glial and glial-glial interactions following axon injury. Prog Neurobiol 1998;55: 1–26.PubMedCrossRefGoogle Scholar
  15. 15.
    Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005;308: 1314–1318.PubMedCrossRefGoogle Scholar
  16. 16.
    Rossi DJ, Brady JD, Mohr C. Astrocyte metabolism and signaling during brain ischemia. Nat Neurosci 2007;10: 1377–1386.PubMedCrossRefGoogle Scholar
  17. 17.
    Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007;10: 1387–1394.PubMedCrossRefGoogle Scholar
  18. 18.
    Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 2007;10: 1361–1368.PubMedCrossRefGoogle Scholar
  19. 19.
    McMahon SB, Malcangio M. Current challenges in glia-pain biology. Neuron 2009;64: 46–54.PubMedCrossRefGoogle Scholar
  20. 20.
    Ren K, Dubner R. Neuron-glia crosstalk gets serious: role in pain hypersensitivity. Curr Opin Anaesthesiol 2008;21: 570–579.PubMedCrossRefGoogle Scholar
  21. 21.
    Hansson E. Could chronic pain and spread of pain sensation be induced and maintained by glial activation? Acta Physiol (Oxf) 2006;187: 321–327.CrossRefGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    Suter MR, Wen YR, Decosterd I, Ji RR. Do glial cells control pain? Neuron Glia Biol 2007;3: 255–268.PubMedCrossRefGoogle Scholar
  24. 24.
    Watkins LR, Hutchinson MR, Ledeboer A, et al. Norman Cousins Lecture. Glia as the “bad guys”: implications for improving clinical pain control and the clinical utility of opioids. Brain Behav Immun 2007;21: 131–146.PubMedCrossRefGoogle Scholar
  25. 25.
    Romero-Sandoval EA, Horvath RJ, DeLeo JA. Neuroimmune interactions and pain: focus on glial-modulating targets. Curr Opin Investig Drugs 2008;9: 726–734.PubMedGoogle Scholar
  26. 26.
    Hald A. Spinal astrogliosis in pain models: cause and effects. Cell Mol Neurobiol 2009;29: 609–619.PubMedCrossRefGoogle Scholar
  27. 27.
    Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 2009;10: 23–36.PubMedCrossRefGoogle Scholar
  28. 28.
    Halassa MM, Fellin T, Takano H, Dong JH, Haydon PG. Synaptic islands defined by the territory of a single astrocyte. J Neurosci 2007;27: 6473–6477.PubMedCrossRefGoogle Scholar
  29. 29.
    Garrison CJ, Dougherty PM, Kajander KC, Carlton SM. Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res 1991;565: 1–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Colburn RW, Rickman AJ, DeLeo JA. The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp Neurol 1999;157: 289–304.PubMedCrossRefGoogle Scholar
  31. 31.
    Zhuang ZY, Wen YR, Zhang DR, 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.PubMedCrossRefGoogle Scholar
  32. 32.
    Guo W, Wang H, Watanabe M, et al. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci 2007;27: 6006–6018.PubMedCrossRefGoogle Scholar
  33. 33.
    Wei F, Guo W, Zou S, Ren K, Dubner R. Supraspinal glial-neuronal interactions contribute to descending pain facilitation. J Neurosci 2008;28: 10482–10495.PubMedCrossRefGoogle Scholar
  34. 34.
    Raghavendra V, Tanga FY, DeLeo JA. Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. Eur J Neurosci 2004;20: 467–473.PubMedCrossRefGoogle Scholar
  35. 35.
    Sweitzer SM, Colburn RW, Rutkowski M, DeLeo JA. Acute peripheral inflammation induces moderate glial activation and spinal IL-lbeta expression that correlates with pain behavior in the rat. Brain Res 1999;829: 209–221.PubMedCrossRefGoogle Scholar
  36. 36.
    Gao YJ, Cheng JK, Zeng Q, et al. Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model. Exp Neurol 2009;219: 146–55.PubMedCrossRefGoogle Scholar
  37. 37.
    Fujita M, Andoh T, Ohashi K, et al. Roles of kinin B1 and B2 receptors in skin cancer pain produced by orthotopic melanoma inoculation in mice. Eur J Pain 2010;14: 588–594.PubMedCrossRefGoogle Scholar
  38. 38.
    Zhang HW, Iida Y, Andoh T, et al. Mechanical hypersensitivity and alterations in cutaneous nerve fibers in a mouse model of skin cancer pain. J Pharmacol Sci 2003;91: 167–170.PubMedCrossRefGoogle Scholar
  39. 39.
    Schwei MJ, Honore P, Rogers SD, et al. Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. J Neurosci 1999;19: 10886–10897.PubMedGoogle Scholar
  40. 40.
    Hald A, Nedergaard S, Hansen RR, Ding M, Heegaard AM. Differential activation of spinal cord glial cells in murine models of neuropathic and cancer pain. Eur J Pain 2009;13: 138–145.PubMedCrossRefGoogle Scholar
  41. 41.
    Zhang RX, Liu B, Wang L, et al. Spinal glial activation in a new rat model of bone cancer pain produced by prostate cancer cell inoculation of the tibia. Pain 2005;118: 125–136.PubMedCrossRefGoogle Scholar
  42. 42.
    Ma W, Quirion R. Partial sciatic nerve ligation induces increase in the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in astrocytes in the lumbar spinal dorsal horn and the gracile nucleus. Pain 2002;99: 175–184.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhang J, De Koniuck Y. Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J Neurochem 2006;97: 772–783.PubMedCrossRefGoogle Scholar
  44. 44.
    Tanga FY, Raghavendra V, DeLeo JA. Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem Int 2004;45: 397–407.PubMedCrossRefGoogle Scholar
  45. 45.
    Cavaliere C, Cirillo G, Rosaria Bianco M, et al. Gliosis alters expression and uptake of spinal glial amiuo acid transporters in a mouse neuropathic pain model. Neuron Glia Biol 2007;3: 141–153.PubMedCrossRefGoogle Scholar
  46. 46.
    Svensson M, Eriksson NP, Aldskogius H. Evidence for activation of astrocytes via reactive microglial cells following hypoglossal nerve transection. J Neurosci Res 1993;35: 373–381.PubMedCrossRefGoogle Scholar
  47. 47.
    Miyoshi K, Obata K, Kondo T, Okamura H, Noguchi K. Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. J Neurosci 2008;28: 12775–12787.PubMedCrossRefGoogle Scholar
  48. 48.
    Garrison CJ, Dougherty PM, Carlton SM. GFAP expression in lumbar spinal cord of naive and neuropathic rats treated with MK-801. Exp Neurol 1994;129: 237–243.PubMedCrossRefGoogle Scholar
  49. 49.
    Chen JJ, Lue JH, Lin LH, et al. Effects of pre-emptive drug treatment on astrocyte activation in the cuneate nucleus following rat median nerve injury. Pain 2010;148: 158–166.PubMedCrossRefGoogle Scholar
  50. 50.
    Colburn RW, DeLeo JA, Rickman AJ, et al. Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J Neuroimmnunol 1997;79: 163–175.CrossRefGoogle Scholar
  51. 51.
    Kim DS, Figueroa KW, Li KW, et al. Profiling of dynamically changed gene expression in dorsal root ganglia post peripheral nerve injury and a critical role of injury-induced glial fibrillary acidic protein in maintenance of pain behaviors [corrected]. Pain 2009;143: 114–122.PubMedCrossRefGoogle Scholar
  52. 52.
    Gao YJ, Zhang L, Samad OA, et al. JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci 2009;29: 4096–4108.PubMedCrossRefGoogle Scholar
  53. 53.
    Weyerbacher AR, Xu Q, Tamasdan C, Shin SJ, Inturrisi CE. N-Methyl-D-aspartate receptor (NMDAR) independent maintenance of inflammatory pain. Pain 2010;148: 237–246.PubMedCrossRefGoogle Scholar
  54. 54.
    Svensson CI, Brodin E. Spinal astrocytes in pain processing: non-neuronal cells as therapeutic targets. Mol Interv 2010;10: 25–38.PubMedCrossRefGoogle Scholar
  55. 55.
    Svensson CI, Zattoni M, Serhan CN. Lipoxius and aspirin-triggered lipoxin inhibit inflammatory pain processing. J Exp Med 2007;204: 245–252.PubMedCrossRefGoogle Scholar
  56. 56.
    Gao YJ, Xu ZZ, Liu YC, et al. The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition. Pain 2010;148: 309–319.PubMedCrossRefGoogle Scholar
  57. 57.
    Hofstetter CP, Holmstrom NA, Lilja JA, et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci 2005;8: 346–353.PubMedCrossRefGoogle Scholar
  58. 58.
    Davies JE, Proschel C, Zhang N, et al. Transplanted astrocytes derived from BMP- or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury. J Biol 2008;7: 24.PubMedCrossRefGoogle Scholar
  59. 59.
    Gao YJ, Zhang L, Ji RR. Spinal injection of TNF-α-activated astrocytes produces persistent pain symptom-mechanical allodynia by releasing monocyte chemoattractant protein-1. Glia 2010 (in press).Google Scholar
  60. 60.
    Meiler ST, Dykstra C, Grzybycki D, Murphy S, Gebhart GF. The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat. Neuropharmacology 1994;33: 1471–1478.CrossRefGoogle Scholar
  61. 61.
    Watkius LR, Martin D, Ulrich P, Tracey KJ, Maier SF. Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain 1997;71: 225–235.CrossRefGoogle Scholar
  62. 62.
    Milligan ED, Twining C, Chacur M, et al. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci 2003;23: 1026–1040.PubMedGoogle Scholar
  63. 63.
    Obata H, Eisenach JC, Hussain H, Bynum T, Vincier M. Spinal glial activation contributes to postoperative mechanical hypersensitivity in the rat. J Pain 2006;7: 816–822.PubMedCrossRefGoogle Scholar
  64. 64.
    Clark AK, Gentry C, Bradbury EJ, McMahon SB, Malcangio M. Role of spinal microglia in rat models of peripheral nerve injury and inflammation. Eur J Pain 2007;11: 223–230.PubMedCrossRefGoogle Scholar
  65. 65.
    Okada-Ogawa A, Suzuki I, Sessle BJ, et al. Astroglia in medullary dorsal horn (trigeminal spinal subnucleus caudalis) are involved in trigeminal neuropathic pain mechanisms. J Neurosci 2009: 29: 11161–11171.PubMedCrossRefGoogle Scholar
  66. 66.
    Ledeboer A, Mahoney JH, Milligan ED, et al. Spinal cord glia and interleukin-1 do not appear to mediate persistent allodynia induced by intramuscular acidic saline in rats. J Pain 2006;7: 757–767.PubMedCrossRefGoogle Scholar
  67. 67.
    Huck S, Grass F, Hortnagl H. The glutamate analogue alpha-aminoadipic acid is taken up by astrocytes before exerting its gliotoxic effect in vitro. J Neurosci 1984;4: 2650–2657.PubMedGoogle Scholar
  68. 68.
    Khurgel M, Koo AC, Ivy GO. Selective ablation of astrocytes by intracerebral injections of alpha-aminoadipate. Glia 1996;16: 351–358.PubMedCrossRefGoogle Scholar
  69. 69.
    Rodriguez MJ, Martinez-Sanchez M, Bernal F, Mahy N. Heterogeneity between hippocampal and septal astroglia as a contributing factor to differential in vivo AMPA excitotoxicity. J Neurosci Res 2004;77: 344–353.PubMedCrossRefGoogle Scholar
  70. 70.
    Wang W, Wang W, Mei X, et al. Crosstalk between spinal astrocytes and neurons in nerve injury-induced neuropathic pain. PLoS One 2009;4: e6973.PubMedCrossRefGoogle Scholar
  71. 71.
    Beart PM, O’Shea RD. Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement. Br J Pharmacol 2007;150: 5–17.PubMedCrossRefGoogle Scholar
  72. 72.
    Huang YH, Bergles DE. Glutamate transporters bring competition to the synapse. Curr Opin Neurobiol 2004;14: 346–352.PubMedCrossRefGoogle Scholar
  73. 73.
    Tawfik VL, Lacroix-Fralish ML, Bercury KK, et al. Induction of astrocyte differentiation by propentofylline increases glutamate transporter expression in vitro: heterogeneity of the quiescent phenotype. Glia 2006;54: 193–203.PubMedCrossRefGoogle Scholar
  74. 74.
    Rothstein JD, Dykes-Hoberg M, Pardo CA, et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 1996;16: 675–686.PubMedCrossRefGoogle Scholar
  75. 75.
    Tanaka K, Watase K, Manabe T, et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 1997;276: 1699–702.PubMedCrossRefGoogle Scholar
  76. 76.
    Katagiri H, Tanaka K, Manabe T. Requirement of appropriate glutamate concentrations in the synaptic cleft for hippocampal LTP induction. Eur J Neurosci 2001;14: 547–553.PubMedCrossRefGoogle Scholar
  77. 77.
    Levenson J, Weeber E, Selcher JC, et al. Long-term potentiation and contextual fear conditioning increase neuronal glutamate uptake. Nat Neurosci 2002;5: 155–161.PubMedCrossRefGoogle Scholar
  78. 78.
    Sung B, Lim G, Mao J. Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci 2003;23: 2899–2910.PubMedGoogle Scholar
  79. 79.
    Wang W, Wang W, Wang Y, et al. Temporal changes of astrocyte activation and glutamate transporter-1 expression in the spinal cord after spinal nerve ligation-induced neuropathic pain. Anat Rec (Hoboken) 2008;291: 513–518.Google Scholar
  80. 80.
    Xin WJ, Weng HR, Dougherty PM. Plasticity in expression of the glutamate transporters GLT-1 and GLAST in spinal dorsal horn glial cells following partial sciatic nerve ligation. Mol Pain 2009;5: 15.PubMedCrossRefGoogle Scholar
  81. 81.
    Tawfik VL, Regan MR, Haenggeli C, et al. Propentofylline-induced astrocyte modulation leads to alterations in glial glutamate promoter activation following spinal nerve transection. Neuroscience 2008;152: 1086–1092.PubMedCrossRefGoogle Scholar
  82. 82.
    Liaw WJ, Stephens RL, Jr., Binns BC, et al. Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. Pain 2005;115: 60–70.PubMedCrossRefGoogle Scholar
  83. 83.
    Weng HR, Chen JH, Cata JP. Inhibition of glutamate uptake in the spinal cord induces hyperalgesia and increased responses of spinal dorsal horn neurons to peripheral afferent stimulation. Neuroscience 2006;138: 1351–1360.PubMedCrossRefGoogle Scholar
  84. 84.
    Maeda S, Kawamoto A, Yatani Y, et al. Gene transfer of GLT-1, a gliai glutamate transporter, into the spinal cord by recombinant adenovirus attenuates inflammatory and neuropathic pain in rats. Mol Pain 2008;4: 65.PubMedCrossRefGoogle Scholar
  85. 85.
    Chiang CY, Wang J, Xie YF, et al. Astroglial glutamate-glutamine shuttle is involved in central sensitization of nociceptive neurons in rat medullary dorsal horn. J Neurosci 2007;27: 9068–76.PubMedCrossRefGoogle Scholar
  86. 86.
    Kozai T, Yamanaka H, Dai Y, et al. Tissue type plasminogen activator induced in rat dorsal horn astrocytes contributes to mechanical hypersensitivity following dorsal root injury. Glia 2007;55: 595–603.PubMedCrossRefGoogle Scholar
  87. 87.
    Bruno MA, Cuello AC. Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. Proc Natl Acad Sci U S A 2006;103: 6735–6740.PubMedCrossRefGoogle Scholar
  88. 88.
    Pang PT, Teng HK, Zaitsev E, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 2004;306: 487–491.PubMedCrossRefGoogle Scholar
  89. 89.
    Hoffman KB, Martinez J, Lynch G. Proteolysis of cell adhesion molecules by serine proteases: a role in long term potentiation? Brain Res 1998;811: 29–33.PubMedCrossRefGoogle Scholar
  90. 90.
    Qian Z, Gilbert ME, Colicos MA, Kandel ER, Kuhl D. Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation. Nature 1993;361: 453–457.PubMedCrossRefGoogle Scholar
  91. 91.
    Blomstrand F, Khatibi S, Muyderman H, et al. 5-Hydroxytryptamine and glutamate modulate velocity and extent of intercellular calcium signalling in hippocampal astroglial cells in primary cultures. Neuroscience 1999;88: 1241–1253.PubMedCrossRefGoogle Scholar
  92. 92.
    Haydon PG. GLIA: listening and talking to the synapse. Nat Rev Neurosci 2001;2: 185–193.PubMedCrossRefGoogle Scholar
  93. 93.
    Giaume C, McCarthy KD. Control of gap-junctional communication in astrocytic networks. Trends Neurosci 1996;19: 319–325.PubMedCrossRefGoogle Scholar
  94. 94.
    Nagy JI, Dudek FE, Rash JE. Update on connexins and gap junctions in neurons and glia in the mammalian nervous system. Brain Res Brain Res Rev 2004;47: 191–215.PubMedCrossRefGoogle Scholar
  95. 95.
    Rohlmann A, Laskawi R, Hofer A, et al. Facial nerve lesions lead to increased immunostaining of the astrocytic gap junction protein (connexin 43) in the corresponding facial nucleus of rats. Neurosci Lett 1993;154: 206–208.PubMedCrossRefGoogle Scholar
  96. 96.
    Lee IH, Lindqvist E, Kiehn O, Widenfalk J, Olson L. Glial and neuronal connexin expression patterns in the rat spinal cord during development and following injury. J Comp Neurol 2005;489: 1–10.PubMedCrossRefGoogle Scholar
  97. 97.
    Qin M, Wang JJ, Cao R, et al. The lumbar spinal cord glial cells actively modulate subcutaneous formalin induced hyperalgesia in the rat. Neurosci Res 2006;55: 442–450.PubMedCrossRefGoogle Scholar
  98. 98.
    Spataro LE, Sloane EM, Milligan ED, et al. Spinal gap junctions: potential involvement in pain facilitation. J Pain 2004;5: 392–405.PubMedCrossRefGoogle Scholar
  99. 99.
    Lan L, Yuan H, Duau L, et al. Blocking the glial function suppresses subcutaneous formalin-induced nociceptive behavior in he rat. Neurosci Res 2007;57: 112–129.PubMedCrossRefGoogle Scholar
  100. 100.
    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.PubMedCrossRefGoogle Scholar
  101. 101.
    Peters CM, Rogers SD, Pomonis JD, et al. Endothelin receptor expression in the normal and injured spinal cord: potential involvement in injury-induced ischemia and gliosis. Exp Neurol 2003;180: 1–13.PubMedCrossRefGoogle Scholar
  102. 102.
    Madiai F, Goettl VM, Hussain SR, et al. Anti-fibroblast growth factor-2 antibodies attenuate mechanical allodynia in a rat model of neuropathic pain. J Mol Neurosci 2005;27: 315–324.PubMedCrossRefGoogle Scholar
  103. 103.
    Madiai F, Hussain SR, Goettl VM, et al. Upregulation of FGF-2 in reactive spinal cord astrocytes following unilateral lumbar spinal nerve ligation. Exp Brain Res 2003;148: 366–376.PubMedGoogle Scholar
  104. 104.
    Garry EM, Delaney A, Blackburn-Munro G, et al. Activation of p38 and p42/44 MAP kinase in neuropathic pain: involvement of VPAC2 and NK2 receptors and mediation by spinal glia. Mol Cell Neurosci 2005;30: 523–537.PubMedCrossRefGoogle Scholar
  105. 105.
    Knerlich-Lukoschus F, Juraschek M, Blomer U, et al. Force-dependent development of neuropathic central pain and time-related CCL2/CCR2 expression after graded spinal cord contusion injuries of the rat. J Neurotrauma 2008;25: 427–448.PubMedCrossRefGoogle Scholar
  106. 106.
    Kawasaki Y, Zhang L, Cheng JK, Ji RR. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, iuterleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci 2008;28: 5189–5194.PubMedCrossRefGoogle Scholar
  107. 107.
    Zhang RX, Li A, Liu B, et al. IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain 2008;135: 232–239.PubMedCrossRefGoogle Scholar
  108. 108.
    DeLeo JA, Colburn RW, Rickman AJ. Cytokine and growth factor immunohistochemical spinal profiles in two animal models of mononeuropathy. Brain Res 1997;759: 50–57.PubMedCrossRefGoogle Scholar
  109. 109.
    Fu D, Guo Q, Ai Y, et al. Glial activation and segmental upregulation of interleukin-lbeta (IL-1beta) in the rat spinal cord after surgical incision. Neurochein Res 2006;31: 333–340.CrossRefGoogle Scholar
  110. 110.
    Milligan ED, O’Connor KA, Nguyen KT, et al. Intrathecal HIV-1 envelope glycoprotein gp120 induces enhanced pain states mediated by spinal cord proinflammatory cytokines. J Neurosci 2001;21: 2808–2819.PubMedGoogle Scholar
  111. 111.
    Sweitzer S, Martin D, DeLeo JA. Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain. Neuroscience 2001;103: 529–539.PubMedCrossRefGoogle Scholar
  112. 112.
    Wolf G, Gabay E, Tal M, Yirmiya R, Shavit Y. Genetic impairment of interleukin-1 signaling attenuates neuropathic pain, autotomy, and spontaneous ectopic neuronal activity, following nerve injury in mice. Pain 2006;120: 315–324.PubMedCrossRefGoogle Scholar
  113. 113.
    Ji GC, Zhang YQ, Ma F, Wu GC. Increase of nociceptive threshold induced by intrathecal injection of interleukin-1 beta in normal and carrageenan inflammatory rat. Cytokine 2002;19: 31–36.PubMedCrossRefGoogle Scholar
  114. 114.
    Kawasaki Y, Xu ZZ, Wang X, et al. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med 2008;14: 331–336.PubMedCrossRefGoogle Scholar
  115. 115.
    Tadano T, Namioka M, Nakagawasai O, et al. Induction of nociceptive responses by intrathecal injection of interleukin-1 in mice. Life Sci 1999: 65: 255–261.PubMedCrossRefGoogle Scholar
  116. 116.
    Sung CS, Wen ZH, Chang WK, et al. Intrathecal interleukin-1beta administration induces thermal hyperalgesia by activating inducible nitric oxide synthase expression in the rat spinal cord. Brain Res 2004;1015: 145–153.PubMedCrossRefGoogle Scholar
  117. 117.
    Reeve AJ, Patel S, Fox A, Walker K, Urban L. Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat. Eur J Pain 2000;4: 247–257.PubMedCrossRefGoogle Scholar
  118. 118.
    Tsakiri N, Kimber I, Rothwell NJ, Pinteaux E. Interleukin-1-induced interleukin-6 synthesis is mediated by the neutral sphingomyelinase/Src kinase pathway in neurones. Br J Pharmacol 2008;153: 775–783.PubMedCrossRefGoogle Scholar
  119. 119.
    Zhang RX, Liu B, Li A, et al. Interleukin 1beta facilitates bone cancer pain in rats by enhancing NMDA receptor NR-1 subunit phosphorylation. Neuroscience 2008;154: 1533–1558.PubMedCrossRefGoogle Scholar
  120. 120.
    Binshtok AM, Wang H, Zimmermann K, et al. Nociceptors are interleukin-1beta sensors. J Neurosci 2008;28: 14062–14073.PubMedCrossRefGoogle Scholar
  121. 121.
    Coull JA, Beggs S, Boudreau D, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005;438: 1017–1021.PubMedCrossRefGoogle Scholar
  122. 122.
    Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288: 1765–1769.PubMedCrossRefGoogle Scholar
  123. 123.
    Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001;410: 471–475.PubMedCrossRefGoogle Scholar
  124. 124.
    Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia 2002;39: 279–291.PubMedCrossRefGoogle Scholar
  125. 125.
    Parks WC, Wilson CL, Lopez-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 2004;4: 617–629.PubMedCrossRefGoogle Scholar
  126. 126.
    Yong VW. Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat Rev Neurosci 2005;6: 931–944.PubMedCrossRefGoogle Scholar
  127. 127.
    Manicone AM, McGuire JK. Matrix metalloproteinases as modulators of inflammation. Semin Cell Dev Biol 2008;19: 34–41.PubMedCrossRefGoogle Scholar
  128. 128.
    Schonbeck U, Mach F, Libby P. Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. J Immunol 1998;161: 3340–3346.PubMedGoogle Scholar
  129. 129.
    Croitoru-Lamoury J, Guillemin GJ, Boussin FD, et al. Expression of chemokines and their receptors in human and simian astrocytes: evidence for a central role of TNF alpha and IFN gamma in CXCR4 and CCR5 modulation. Glia 2003;41: 354–370.PubMedCrossRefGoogle Scholar
  130. 130.
    Meeuwsen S, Persoon-Deen C, Bsibsi M, Ravid R, van Noort JM. Cytokine, chemokine and growth factor gene profiling of cultured human astrocytes after exposure to proinflammatory stimuli. Glia 2003;43: 243–253.PubMedCrossRefGoogle Scholar
  131. 131.
    El-Hage N, Gurwell JA, Singh IN, et al. Synergistic increases in intracellular Ca2+, and the release of MCP-1, RANTES, and IL-6 by astrocytes treated with opiates and HIV-1 Tat. Glia 2005;50: 91–106.PubMedCrossRefGoogle Scholar
  132. 132.
    Mojsilovic-Petrovic J, Callaghan D, Cui H, et al. Hypoxia-inducible factor-1 (HIF-1) is involved in the regulation of hypoxia-stimulated expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and MCP-5 (Cell2) in astrocytes. J Neuroinflammation 2007;4: 12.PubMedCrossRefGoogle Scholar
  133. 133.
    Van Der Voorn P, Tekstra J, Beelen RH, et al. Expression of MCP-1 by reactive astrocytes in demyelinating multiple, sclerosis lesions. Am J Pathol 1999;154: 45–51.CrossRefGoogle Scholar
  134. 134.
    Tanuma N, Sakuma H, Sasaki A, Matsumoto Y. Chemokine expression by astrocytes plays a role in microglia/macrophage activation and subsequent neurodegeneration in secondary progressive multiple sclerosis. Acta Neuropathol 2006;112: 195–204.PubMedCrossRefGoogle Scholar
  135. 135.
    Huang D, Han Y, Rani MR, et al. Chemokines and chemokine receptors in inflammation of the nervous system: manifold roles and exquisite regulation. Immunol Rev 2000;177: 52–67.PubMedCrossRefGoogle Scholar
  136. 136.
    Babcock AA, Kuziel WA, Rivest S, Owens T. Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J Neurosci 2003;23: 7922–7930.PubMedGoogle Scholar
  137. 137.
    Yan YP, Sailor KA, Lang BT, et al. Monocyte chemoattractant protein-1 plays a critical role in neuroblast migration after focal cerebral ischemia. J Cereb Blood Flow Metab 2007;27: 1213–1224.PubMedCrossRefGoogle Scholar
  138. 138.
    White FA, Sun J, Waters SM, et al. Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. Proc Natl Acad Sci U S A 2005: 102: 14092–14097.PubMedCrossRefGoogle Scholar
  139. 139.
    Gosseliu RD, Varela C, Banisadr G, et al. Constitutive expression of CCR2 chemokine receptor and inhibition by MCP-1/CCL2 of GABA-induced currents in spinal cord neurones. J Neurochem 2005: 95: 1023–1034.CrossRefGoogle Scholar
  140. 140.
    Gao YJ, Ji RR. c-Fos and pERK, which is a better marker for neuronal activation and central sensitization after noxious stimulation and tissue injury? Open Pain J 2009;2: 11–7.PubMedCrossRefGoogle Scholar
  141. 141.
    Thacker MA, Clark AK, Bishop T, et al. CCL2 is a key mediator of microglia activation in neuropathic pain states. Eur J Pain 2009: 13: 263–272.PubMedCrossRefGoogle Scholar
  142. 142.
    Abbadie C, Lindia JA, Cumiskey AM, et al. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc Natl Acad Sci U S A 2003: 100: 7947–7952.PubMedCrossRefGoogle Scholar
  143. 143.
    Zhang J, Shi XQ, Echeverry S, et al. Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neurosci 2007;27: 12396–12406.PubMedCrossRefGoogle Scholar
  144. 144.
    Bhangoo S, Ren D, Miller RJ, et al. Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors. Mol Pain 2007;3: 38.PubMedCrossRefGoogle Scholar
  145. 145.
    Bhangoo SK, Ripsch MS, Buchanan DJ, Miller RJ, White FA. Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy. Mol Pain 2009;5: 48.PubMedCrossRefGoogle Scholar
  146. 146.
    Ji RR, Gereau RWt, Malcangio M, Strichartz GR. MAP kinase and pain. Brain Res Rev 2009;60: 135–148.PubMedCrossRefGoogle Scholar
  147. 147.
    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.PubMedGoogle Scholar
  148. 148.
    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.PubMedCrossRefGoogle Scholar
  149. 149.
    Weyerbacher AR, Xu Q, Tamasdan C, Shin SJ, Inturrisi CE. N-Methyl-d-aspartate receptor (NMDAR) independent maintenance of inflammatory pain. Pain 2010;148: 237–246.PubMedCrossRefGoogle Scholar
  150. 150.
    Migheli A, Piva R, Atzori C, Troost D, Schiffer D. c-Jun, JNK/ SAPK kinases and transcription factor NF-kappa B are selectively activated in astrocytes, but not motor neurons, in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 1997;56: 1314–1322.PubMedCrossRefGoogle Scholar
  151. 151.
    Obata K, Yamanaka H, Kobayashi K, et al. Role of mitogenactivated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation. J Neurosci 2004;24: 10211–10222.PubMedCrossRefGoogle Scholar
  152. 152.
    Daulhac L, Mallet C, Courteix C, et al. Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-rnetbyl-D-aspartate~dependent mechanisms. Mol Pharmacol 2006;70: 1246–1254.PubMedCrossRefGoogle Scholar
  153. 153.
    Falsig J, Porzgen P, Lotharius J, Leist M. Specific modulation of astrocyte inflammation by inhibition of mixed lineage kinases with CEP-1347. J Immunol 2004;173: 2762–2770.PubMedGoogle Scholar
  154. 154.
    Gao YJ, Ji RR. Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther 2010;126: 56–68.PubMedCrossRefGoogle Scholar
  155. 155.
    Katsura H, Obata K, Miyoshi K, et al. Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury. Glia 2008;56: 723–733.PubMedCrossRefGoogle Scholar
  156. 156.
    Ferrara N, Ousley F, Gospodarowicz D. Bovine brain astrocytes express basic fibroblast growth factor, a neurotropic and angiogenic mitogen. Brain Res 1988;462: 223–232.PubMedCrossRefGoogle Scholar
  157. 157.
    Eclancher F, Perraud F, Faltin J, Labourdette G, Sensenbrenner M. Reactive astrogliosis after basic fibroblast growth factor (bFGF) injection in injured neonatal rat brain. Glia 1990;3: 502–509.PubMedCrossRefGoogle Scholar
  158. 158.
    Takano T, Oberheim N, Cotrina ML, Nedergaard M. Astrocytes and ischemic injury. Stroke 2009;40: S8-S12.PubMedCrossRefGoogle Scholar
  159. 159.
    Hayakawa K, Nakano T, Irie K, et al. Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice. J Cereb Blood Flow Metab 2010;30: 871–882.PubMedCrossRefGoogle Scholar
  160. 160.
    Borsello T, Clarke PG, Hirt L, et al. A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med 2003;9: 1180–1186.PubMedCrossRefGoogle Scholar
  161. 161.
    Davis JE, Gabler NK, Walker-Daniels J, Spurlock ME. The c-Jun N-terminal kinase mediates the induction of oxidative stress and insulin resistance by palmitate and toll-like receptor 2 and 4 ligands in 3T3-L1 adipocytes. Florin Metab Res 2009: 41: 523–530.CrossRefGoogle Scholar
  162. 162.
    Ijaz A, Tejada T, Catanuto P, et al. Inhibition of C-jun N-terminal kinase improves insulin sensitivity but worsens albuminuria in experimental diabetes. Kidney Int 2009: 75: 381–388.PubMedCrossRefGoogle Scholar
  163. 163.
    Oberheim NA, Takano T, Han X, et al. Uniquely hominid features of adult human astrocytes. J Neurosci 2009: 29: 3276–3287.PubMedCrossRefGoogle Scholar
  164. 164.
    Oberheim NA, Wang X, Goldman S, Nedergaard M. Astrocytic complexity distinguishes the human brain. Trends Neurosci 2006;29: 547–553.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  1. 1.Department of Anesthesiology, Sensory Plasticity Laboratory, Pain Research CenterBrigham and Women’s Hospital and Harvard Medical SchoolBoston

Personalised recommendations