International Journal of Oral Biology

The Korean Academy of Oral Biology (대한구강생물학회)
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Role of microglial activation on neuronal excitability in rat substantia gelatinosa

  • Park, Areum (Department of Dental Hygiene, Gangdong University) ;
  • Chun, Sang Woo (Department of Oral Physiology, College of Dentistry, Wonkwang Dental Research Institute, Wonkwang University)
  • Received : 2020.12.07
  • Accepted : 2020.12.17
  • Published : 2020.12.31
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Abstract

Glial cells, including astrocytes and microglia, interact closely with neurons and modulate pain transmission, particularly under pathological conditions. In this study, we examined the excitability of substantia gelatinosa (SG) neurons of the spinal dorsal horn using a patch clamp recording to investigate the roles of microglial activation in the nociceptive processes of rats. We used xanthine/xanthine oxidase (X/XO), a generator of superoxide anion (O2·-), to induce a pathological pain condition. X/XO treatment induced an inward current and membrane depolarization. The inward current was significantly inhibited by minocycline, a microglial inhibitor, and fluorocitrate, an astrocyte inhibitor. To examine whether toll-like receptor 4 (TLR4) in microglia was involved in the inward current, we used lipopolysaccharide (LPS), a highly specific TLR4 agonist. The LPS induced inward current, which was decreased by pretreatment with Tak-242, a TLR4-specific inhibitor, and phenyl N-t-butylnitrone, a reactive oxygen species scavenger. The X/XO-induced inward current was also inhibited by pretreatment with Tak-242. These results indicate that the X/XO-induced inward current of SG neurons occurs through activation of TLR4 in microglial cells, suggesting that neuroglial cells modulate the nociceptive process through central sensitization.

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References

  1. Yoshimura M, Jessell TM. Membrane properties of rat substantia gelatinosa neurons in vitro. J Neurophysiol 1989;62:109-18. doi: 10.1152/jn.1989.62.1.109.
  2. Kallenborn-Gerhardt W, Schroder K, Geisslinger G, Schmidtko A. NOXious signaling in pain processing. Pharmacol Ther 2013;137:309-17. doi: 10.1016/j.pharmthera.2012.11.001.
  3. Schwartz ES, Lee I, Chung K, Chung JM. Oxidative stress in the spinal cord is an important contributor in capsaicin-induced mechanical secondary hyperalgesia in mice. Pain 2008;138:514-24. doi: 10.1016/j.pain.2008.01.029.
  4. Kim HY, Lee I, Chun SW, Kim HK. Reactive oxygen species donors increase the responsiveness of dorsal horn neurons and induce mechanical hyperalgesia in rats. Neural Plast 2015;2015:293423. doi: 10.1155/2015/293423.
  5. Park A, Chun SW. Pre- and postsynaptic actions of reactive oxygen species and nitrogen species in spinal substantia gelatinosa neurons. Int J Oral Biol 2018;43:209-16. doi: 10.11620/IJOB.2018.43.4.209.
  6. Gao YJ, Ji RR. Targeting astrocyte signaling for chronic pain. Neurotherapeutics 2010;7:482-93. doi: 10.1016/j.nurt.2010.05.016.
  7. Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain 2013;154 Suppl 1:S10-28. doi: 10.1016/j.pain.2013.06.022.
  8. Streit WJ, Mrak RE, Griffin WS. Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 2004;1:14. doi: 10.1186/1742-2094-1-14.
  9. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 2005;8:752-8. doi: 10.1038/nn1472.
  10. Inoue K, Tsuda M. Microglia and neuropathic pain. Glia 2009;57:1469-79. doi: 10.1002/glia.20871.
  11. McMahon SB, Malcangio M. Current challenges in glia-pain biology. Neuron 2009;64:46-54. doi: 10.1016/j.neuron.2009.09.033.
  12. Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 2009;10:23-36. doi: 10.1038/nrn2533.
  13. Gwak YS, Hulsebosch CE. Remote astrocytic and microglial activation modulates neuronal hyperexcitability and belowlevel neuropathic pain after spinal injury in rat. Neuroscience 2009;161:895-903. doi: 10.1016/j.neuroscience.2009.03.055.
  14. Bessis A, Bechade C, Bernard D, Roumier A. Microglial control of neuronal death and synaptic properties. Glia 2007;55:233-8. doi: 10.1002/glia.20459.
  15. Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007;10:1387-94. doi: 10.1038/nn1997.
  16. 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;102:5856-61. doi: 10.1073/pnas.0501634102.
  17. Qin L, Liu Y, Wang T, Wei SJ, Block ML, Wilson B, Liu B, Hong JS. NADPH oxidase mediates lipopolysaccharideinduced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem 2004;279:1415-21. doi: 10.1074/jbc.M307657200.
  18. Bubici C, Papa S, Pham CG, Zazzeroni F, Franzoso G. The NFkappaB-mediated control of ROS and JNK signaling. Histol Histopathol 2006;21:69-80. doi: 10.14670/HH-21.69.
  19. Kim HY, Chung JM, Chung K. Increased production of mitochondrial superoxide in the spinal cord induces pain behaviors in mice: the effect of mitochondrial electron transport complex inhibitors. Neurosci Lett 2008;447:87-91. doi: 10.1016/j.neulet.2008.09.041.
  20. Schwartz ES, Kim HY, Wang J, Lee I, Klann E, Chung JM, Chung K. Persistent pain is dependent on spinal mitochondrial antioxidant levels. J Neurosci 2009;29:159-68. doi: 10.1523/ JNEUROSCI.3792-08.2009.
  21. Khalil Z, Liu T, Helme RD. Free radicals contribute to the reduction in peripheral vascular responses and the maintenance of thermal hyperalgesia in rats with chronic constriction injury. Pain 1999;79:31-7. doi: 10.1016/s0304-3959(98)00143-2.
  22. Kim HK, Kim JH, Gao X, Zhou JL, Lee I, Chung K, Chung JM. Analgesic effect of vitamin E is mediated by reducing central sensitization in neuropathic pain. Pain 2006;122:53-62. doi: 10.1016/j.pain.2006.01.013.
  23. Lee HI, Park AR, Chun SW. Effects of NaOCl on neuronal excitability and intracellular calcium concentration in rat spinal substantia gelatinosa neurons. Int J Oral Biol 2013;38:5-12. doi: 10.11620/IJOB.2013.38.1.005.
  24. Park AR, Lee HI, Semjid D, Kim DK, Chun SW. Dual effect of exogenous nitric oxide on neuronal excitability in rat substantia gelatinosa neurons. Neural Plast 2014;2014:628531. doi: 10.1155/2014/628531.
  25. Adam-Vizi V. Production of reactive oxygen species in brain mitochondria: contribution by electron transport chain and non-electron transport chain sources. Antioxid Redox Signal 2005;7:1140-9. doi: 10.1089/ars.2005.7.1140.
  26. Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 2007;8:57-69. doi: 10.1038/nrn2038.
  27. Gao HM, Zhou H, Hong JS. NADPH oxidases: novel therapeutic targets for neurodegenerative diseases. Trends Pharmacol Sci 2012;33:295-303. doi: 10.1016/j.tips.2012.03.008.
  28. Rojo AI, McBean G, Cindric M, Egea J, Lopez MG, Rada P, Zarkovic N, Cuadrado A. Redox control of microglial function: molecular mechanisms and functional significance. Antioxid Redox Signal 2014;21:1766-801. doi: 10.1089/ars.2013.5745.
  29. 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:E197-205. doi: 10.1073/pnas.1111098109.
  30. Sato E, Mokudai T, Niwano Y, Kohno M. Kinetic analysis of reactive oxygen species generated by the in vitro reconstituted NADPH oxidase and xanthine oxidase systems. J Biochem 2011;150:173-81. doi: 10.1093/jb/mvr051.
  31. Zhou X, Wen K, Yuan D, Ai L, He P. Calcium influx-dependent differential actions of superoxide and hydrogen peroxide on microvessel permeability. Am J Physiol Heart Circ Physiol 2009;296:H1096-107. doi: 10.1152/ajpheart.01037.2008.
  32. Son Y, Chun SW. Effects of hydrogen peroxide on neuronal excitability and synaptic transmission in rat substantia gelatinosa neurons. Int J Oral Biol 2007;32:153-60.
  33. 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;11:223-30. doi: 10.1016/j.ejpain.2006.02.003.
  34. Cho IH, Chung YM, Park CK, Park SH, Lee H, Kim D, Piao ZG, Choi SY, Lee SJ, Park K, Kim JS, Jung SJ, Oh SB. Systemic administration of minocycline inhibits formalin-induced inflammatory pain in rat. Brain Res 2006;1072:208-14. doi: 10.1016/j.brainres.2005.12.039.
  35. Moss A, Beggs S, Vega-Avelaira D, Costigan M, Hathway GJ, Salter MW, Fitzgerald M. Spinal microglia and neuropathic pain in young rats. Pain 2007;128:215-24. doi: 10.1016/j.pain.2006.09.018.
  36. Little JW, Doyle T, Salvemini D. Reactive nitroxidative species and nociceptive processing: determining the roles for nitric oxide, superoxide, and peroxynitrite in pain. Amino Acids 2012;42:75-94. doi: 10.1007/s00726-010-0633-0.
  37. Ficker C, Rozmer K, Kato E, Ando RD, Schumann L, Krugel U, Franke H, Sperlagh B, Riedel T, Illes P. Astrocyte-neuron interaction in the substantia gelatinosa of the spinal cord dorsal horn via P2X7 receptor-mediated release of glutamate and reactive oxygen species. Glia 2014;62:1671-86. doi: 10.1002/glia.22707.
  38. Kim D, Kim YJ, Koh HS, Jang TY, Park HE, Kim JY. Reactive oxygen species enhance TLR10 expression in the human monocytic cell line THP-1. Int J Mol Sci 2010;11:3769-82. doi: 10.3390/ijms11103769.
  39. Gao HM, Jiang J, Wilson B, Zhang W, Hong JS, Liu B. Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson's disease. J Neurochem 2002;81:1285-97. doi: 10. 1046/j.1471-4159.2002.00928.x. https://doi.org/10.1046/j.1471-4159.2002.00928.x