본문 바로가기
KERD
논문KCI 등재

Glial Mechanisms of Neuropathic Pain and Emerging Interventions

2

조회

0

다운로드

1

인용

0

참고문헌

키워드

초록

Neuropathic pain is often refractory to intervention because of the complex etiology and an incomplete understanding of the mechanisms behind this type of pain. Glial cells, specifically microglia and astrocytes, are powerful modulators of pain and new targets of drug development for neuropathic pain. Glial activation could be the driving force behind chronic pain, maintaining the noxious signal transmission even after the original injury has healed. Glia express chemokine, purinergic, toll-like, glutaminergic and other receptors that enable them to respond to neural signals, and they can modulate neuronal synaptic function and neuronal excitability. Nerve injury upregulates multiple receptors in spinal microglia and astrocytes. Microglia influence neuronal communication by producing inflammatory products at the synapse, as do astrocytes because they completely encapsulate synapses and are in close contact with neuronal somas through gap junctions. Glia are the main source of inflammatory mediators in the central nervous system. New therapeutic strategies for neuropathic pain are emerging such as targeting the glial cells, novel pharmacologic approaches and gene therapy. Drugs targeting microglia and astrocytes, cytokine production, and neural structures including dorsal root ganglion are now under study, as is gene therapy. Isoform-specific inhibition will minimize the side effects produced by blocking all glia with a general inhibitor. Enhancing the anti-inflammatory cytokines could prove more beneficial than administering proinflammatory cytokine antagonists that block glial activation systemically. Research on therapeutic gene transfer to the central nervous system is underway, although obstacles prevent immediate clinical application.

Abstract

Neuropathic pain is often refractory to intervention because of the complex etiology and an incomplete understanding of the mechanisms behind this type of pain. Glial cells, specifically microglia and astrocytes, are powerful modulators of pain and new targets of drug development for neuropathic pain. Glial activation could be the driving force behind chronic pain, maintaining the noxious signal transmission even after the original injury has healed. Glia express chemokine, purinergic, toll-like, glutaminergic and other receptors that enable them to respond to neural signals, and they can modulate neuronal synaptic function and neuronal excitability. Nerve injury upregulates multiple receptors in spinal microglia and astrocytes. Microglia influence neuronal communication by producing inflammatory products at the synapse, as do astrocytes because they completely encapsulate synapses and are in close contact with neuronal somas through gap junctions. Glia are the main source of inflammatory mediators in the central nervous system. New therapeutic strategies for neuropathic pain are emerging such as targeting the glial cells, novel pharmacologic approaches and gene therapy. Drugs targeting microglia and astrocytes, cytokine production, and neural structures including dorsal root ganglion are now under study, as is gene therapy. Isoform-specific inhibition will minimize the side effects produced by blocking all glia with a general inhibitor. Enhancing the anti-inflammatory cytokines could prove more beneficial than administering proinflammatory cytokine antagonists that block glial activation systemically. Research on therapeutic gene transfer to the central nervous system is underway, although obstacles prevent immediate clinical application.

참고문헌 (88)

  1. Dworkin RH, "Pain and its persistence in herpes zoster", Pain, 67, pp.241~251 (1996)
  2. McCleane G, "Pharmacological management of neuropathic pain", CNS Drugs, 17, pp.1031~1043 (2003)
  3. Tsuda M, "Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia", Trends Neurosci, 28, pp.101~107 (2005)
  4. Watkins LR, "Glia: a novel drug discovery target for clinical pain", Nat Rev Drug Discov, 2, pp.973~985 (2003)
  5. Sommer C, "Painful neuropathies", Curr Opin Neurol, 16, pp.623~628 (2003)
  6. Campbell JN, "Mechanisms of neuropathic pain", Neuron, 52, pp.77~92 (2006)
  7. Hucho T, "Signaling pathways in sensitization: toward a nociceptor cell biology", Neuron, 55, pp.365~376 (2007)
  8. Woolf CJ, "Neuropathic pain: aetiology, symptoms, mechanisms, and management", Lancet, 353, pp.1959~1964 (1999)
  9. Jolivalt CG, "Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters", Pain, 140, pp.48~57 (2008)
  10. Khasar SG, "Epinephrine produces a beta-adrenergic receptor-mediated mechanical hyperalgesia and in vitro sensitization of rat nociceptors", J Neurophysiol, 81, pp.1104~1112 (1999)
  11. Wieseler-Frank J, "Glial activation and pathological pain", Neurochem Int, 45, pp.389~395 (2004)
  12. Spataro LE, "Spinal gap junctions: potential involvement in pain facilitation", J Pain, 5, pp.392~405 (2004)
  13. Gehrmann J, "Microglia: intrinsic immuneffector cell of the brain", Brain Res Brain Res Rev, 20, pp.269~287 (1995)
  14. Tsuda M, "P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury", Nature, 424, pp.778~783 (2003)
  15. Verge GM, "Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions", Eur J Neurosci, 20, pp.1150~1160 (2004)
  16. Zhuang ZY, "Role of the CX3CR1", p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine, 2007, pp.21, 642~651
  17. Light AR, "Purinergic receptors activating rapid intracellular Ca increases in microglia", Neuron Glia Biol, 2, pp.125~138 (2006)
  18. Tozaki-Saitoh H, "P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury", J Neurosci, 28, pp.4949~4956 (2008)
  19. Abbadie C, "Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2", Proc Natl Acad Sci USA, 100, pp.7947~7952 (2003)
  20. Tanga FY, "The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy", Proc Natl Acad Sci USA, 102, pp.5856~5861 (2005)
  21. Kumar S, "p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases", Nat Rev Drug Discov, 2, pp.717~726 (2003)
  22. Si J, "NADPH oxidase NOX5-S mediates acid-induced cyclooxygenase-2 expression via activation of NF-kappaB in Barrett's esophageal adenocarcinoma cells", J Biol Chem, 282, pp.16244~16255 (2007)
  23. Zhang FY, "Peripheral formalin injection induces long-lasting increases in cyclooxygenase 1 expression by microglia in the spinal cord", J Pain, 8, pp.110~117 (2007)
  24. Jana M, "Induction of tumor necrosis factor-alpha (TNF-alpha) by interleukin- 12 p40 monomer and homodimer in microglia and macrophages", J Neurochem, 86, pp.519~528 (2003)
  25. Krakauer T, "Molecular therapeutic targets in inflammation: cyclooxygenase and NF-kappaB", Curr Drug Targets Inflamm Allergy, 3, pp.317~324 (2004)
  26. Raouf R, "Differential regulation of microglial P2X4 and P2X7 ATP receptors following LPS-induced activation", Neuropharmacology, 53, pp.496~504 (2007)
  27. Hanisch UK, "Microglia as a source and target of cytokines", Glia, 40, pp.140~155 (2002)
  28. Vitkovic L, "“Inflammatory” cytokines: neuromodulators in normal brain?", J Neurochem, 74, pp.457~471 (2000)
  29. Haynes SE, "The P2Y12 receptor regulates microglial activation by extracellular nucleotides", Nat Neurosci, 9, pp.1512~1519 (2006)
  30. Zhuang ZY, "ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model", Pain, 114, pp.149~159 (2005)
  31. Wei F, "Activation of Erk in the anterior cingulate cortex during the induction and expression of chronic pain", Mol Pain, 4, pp.28~28 (2008)
  32. Colburn RW, "Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat", J Neuroimmunol, 79, pp.163~175 (1997)
  33. White FA, "Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion", Proc Natl Acad Sci USA, 102, pp.14092~14097 (2005)
  34. Zhang J, "Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury", J Neurochem, 97, pp.772~783 (2006)
  35. Rebenko-Moll NM, "Chemokines, mononuclear cells and the nervous system: heaven (or hell) is in the details", Curr Opin Immunol, 18, pp.683~689 (2006)
  36. Dansereau MA, "Spinal CCL2 pronociceptive action is no longer effective in CCR2 receptor antagonist-treated rats", J Neurochem, 106, pp.757~769 (2008)
  37. Jung H, "Monocyte chemoattractant protein-1 functions as a neuromodulator in dorsal root ganglia neurons", Neurochem, 104, pp.254~263 (2008)
  38. Thacker MA, "CCL2 is a key mediator of microglia activation in neuropathic pain states", Eur J Pain, 13, pp.263~272 (2009)
  39. Miyake K, "Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors", Semin Immunol, 19, pp.3~10 (2007)
  40. Kim D, "A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity", J Biol Chem, 282, pp.14975~14983 (2007)
  41. Gay NJ, "Structure and function of Toll receptors and their ligands", Annu Rev Biochem, 76, pp.141~165 (2007)
  42. Hutchinson MR, "Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4)", Eur J Neurosci, 28, pp.20~29 (2008)
  43. Garrison CJ, "Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury", Brain Res, 565, pp.1~7 (1991)
  44. Takano T, "Astrocyte-mediated control of cerebral blood flow", Nat Neurosci, 9, pp.260~267 (2006)
  45. Yarowsky P, "Effect of monensin on deoxyglucose uptake in cultured astrocytes: energy metabolism is coupled to sodium entry", J Neurosci, 6, pp.859~866 (1986)
  46. Rogers SD, "Endothelin B receptors are expressed by astrocytes and regulate astrocyte hypertrophy in the normal and injured CNS", Glia, 41, pp.180~190 (2003)
  47. Peters CM, "Endothelin receptor expression in the normal and injured spinal cord: potential involvement in injury-induced ischemia and gliosis", Exp Neurol, 180, pp.1~13 (2003)
  48. Ji RR, "Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity", Nat Neurosci, 2, pp.1114~1119 (1999)
  49. Ji RR, "ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity", J Neurosci, 22, pp.478~485 (2002)
  50. Zhuang ZY, "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, pp.3551~3560 (2006)
  51. Borsello T, "A peptide inhibitor of c-Jun N- terminal kinase protects against excitotoxicity and cerebral ischemia", Nat Med, 9, pp.1180~1186 (2003)
  52. Ferrara N, "Bovine brain astrocytes express basic fibroblast growth factor, a neurotropic and angiogenic mitogen", Brain Res, 462, pp.223~232 (1988)
  53. Eclancher F, "Reactive astrogliosis after basic fibroblast growth factor (bFGF) injection in injured neonatal rat brain", Glia, 3, pp.502~509 (1990)
  54. Koshinaga M, "Altered acidic and basic fibroblast growth factor expression following spinal cord injury", Exp Neurol, 120, pp.32~48 (1993)
  55. Lee TT, "Neuroprotective effects of basic fibroblast growth factor following spinal cord contusion injury in the rat", J Neurotrauma, 16, pp.347~356 (1999)
  56. Rabchevsky AG, "Basic fibroblast growth factor (bFGF) enhances functional recovery following severe spinal cord injury to the rat", Exp Neurol, 164, pp.280~291 (2000)
  57. Miyoshi K, "Interleukin-18-mediated microglia", astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury, 2008, pp.28, 12775~12787
  58. Meller ST, "The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat", Neuropharmacology, 33, pp.1471~1478 (1994)
  59. Raghavendra V, "Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy", J Pharmacol Exp Ther, 306, pp.624~630 (2003)
  60. Ledeboer A, "Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation", Pain, 115, pp.71~83
  61. Hassel B, "Selective inhibition of glial cell metabolism in vivo by fluorocitrate", Brain Res, 576, pp.120~124 (1992)
  62. Aumeerally N, "Glutamate-evoked release of adenosine and regulation of peripheral nociception", Neuroscience, 127, pp.1~11 (2004)
  63. Zhang SC, "Suppression of activated microglia promotes survival and function of transplanted oligodendroglial progenitors", Glia, 41, pp.191~198 (2003)
  64. Romero-Sandoval EA, "Neuroimmune interactions and pain: focus on glial-modulating targets", Curr Opin Investig Drugs, 9, pp.726~734 (2008)
  65. Padi SS, "Minocycline prevents the development of neuropathic pain, but not acute pain: possible anti-inflammatory and antioxidant mechanisms", Eur J Pharmacol, 601, pp.79~87 (2008)
  66. Hutchinson MR, "Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast)", Brain Behav Immun, 23, pp.240~250 (2009)
  67. Tawfik VL, "Efficacy of propentofylline, a glial modulating agent, on existing mechanical allodynia following peripheral nerve injury", Brain Behav Immun, 21, pp.238~246 (2007)
  68. Schäfers M, "Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons", J Neurosci, 23, pp.2517~2521 (2003)
  69. Wen YR, "Nerve conduction blockade in the sciatic nerve prevents but does not reverse the activation of p38 mitogen-activated protein kinase in spinal microglia in the rat spared nerve injury model", Anesthesiology, 107, pp.312~321 (2007)
  70. Milligan ED, "Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats", J Neurosci, 23, pp.1026~1040 (2003)
  71. Margolles-Clark E, "Suramin inhibits the CD40-CD154 costimulatory interaction: a possible mechanism for immunosuppressive effects", Biochem Pharmacol, 77, pp.1236~1245 (2009)
  72. Ji RR, "p38 MAPK, microglial signaling, and neuropathic pain", Mol Pain, 3, pp.33~33 (2007)
  73. Bhat NR, "Extracellular signal-regulated kinase and p38 subgroups of mitogen- activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures", J Neurosci, 18, pp.1633~1641 (1998)
  74. Ji RR, "Protein kinases as potential targets for the treatment of pathological pain", Handb Exp Pharmacol, 177, pp.359~389 (2007)
  75. Pires MM, "Inhibition of P-glycoprotein-mediated paclitaxel resistance by reversibly linked quinine homodimers", Mol Pharmacol, 75, pp.92~100 (2009)
  76. Bettoni I, "Glial TLR4 receptor as new target to treat neuropathic pain: efficacy of a new receptor antagonist in a model of peripheral nerve injury in mice", Glia, 56, pp.1312~1319 (2008)
  77. Borsello T, "Use of cell-permeable peptides to prevent neuronal degeneration", Trends Mol Med, 10, pp.239~244 (2004)
  78. Falsig J, "Specific modulation of astrocyte inflammation by inhibition of mixed lineage kinases with CEP-1347", J Immunol, 173, pp.2762~2770 (2004)
  79. Madiai F, "Anti-fibroblast growth factor-2 antibodies attenuate mechanical allodynia in a rat model of neuropathic pain", J Mol Neurosci, 27, pp.315~324 (2005)
  80. Manzanares J, "Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes", Curr Neuropharmacol, 4, pp.239~257
  81. Ashton JC, "The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration", Curr Neuropharmacol, 5, pp.73~80 (2007)
  82. Beltramo M, "CB2 receptor- mediated antihyperalgesia: possible direct involvement of neural mechanisms", Eur J Neurosci, 23, pp.1530~1538 (2006)
  83. Gunnarsson I, "Development of lupus-related side-effects in patients with early RA during sulphasalazine treatment-the role of IL-10 and HLA", Rheumatology (Oxford), 39, pp.886~893 (2000)
  84. Goss JR, "Gene therapy applications for the treatment of neuropathic pain", Expert Rev Neurother, 7, pp.487~506 (2007)
  85. Mata M, "Gene therapy directed at the neuroimmune component of chronic pain with particular attention to the role of TNF alpha", Neurosci Lett, 437, pp.209~213 (2008)
  86. Milligan ED, "Intrathecal polymer-based interleukin-10 gene delivery for neuropathic pain", Neuron Glia Biol, 2, pp.293~308 (2006)
  87. Tan PH, "More trouble ahead; is gene therapy coming of age?", Expert Opin Biol Ther, 8, pp.561~567 (2008)
  88. Mika J, "Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness", Pharmacol Rep, 60, pp.297~307 (2008)

관련 논문AI추천

이 간행물의 다른 논문 (19건)