EFFECTS OF MANDIBULAR NERVE TRANSECTION ON TRIGEMINAL GANGLION NEURONS AND THE ACTIVATION OF MICROGLIAL CELLS IN THE MEDULLARY DORSAL HORN

하악신경 절삭이 삼차신경절 신경세포와 연수후각 소교세포 활성화에 미치는 영향

  • Lim, Yo-Han (Department of Dentistry, College of Medicine, Catholic University of Korea) ;
  • Choie, Mok-Kyun (Department of Dentistry, College of Medicine, Catholic University of Korea)
  • 임요한 (가톨릭대학교 의과대학 치과학교실) ;
  • 최목균 (가톨릭대학교 의과대학 치과학교실)
  • Published : 2007.06.30

Abstract

Microglial cell activation is known to contribute to neuropathic pain following spinal sensory nerve injuries. In this study, I investigated its mechanisms in the case of trigeminal sensory nerve injuries by which microglial cell and p38 mitogen-activated protein kinase (p38 MAPK) activation in the medullary dorsal horn (MDH) would contribute to the facial pain hypersensitivity following mandibular nerve transection (MNT). And also investigated the changes of trigeminal ganglion neurons and ERK, p38 MAPK manifestations. Activation of microglial cells was monitored at 1, 3, 7, 14, 28 and 60 day using immunohistochemical analyses. Microglial cell activation was primarily observed in the superficial laminae of the MDH. Microglial cell activation was initiated at postoperative 1 day, maximal at 3 day, maintained until 14 day and gradually reduced and returned to the basal level by 60 days after MNT. Pain hypersensitivity was also initiated and attenuated almost in parallel with microglial cell activation pattern. To investigate the contribution of the microglial cell activation to the pain hypersensitivity, minocycline, an inhibitor of microglial cell activation by means of p38 MAPK inhibition, was administered. Minocycline dose-dependently attenuated the development of the pain hypersensitivity in parallel with inhibition of microglial cell and p38 MAPK activation following MNT. Mandibular nerve transection induced the activation of ERK, but did not p38 MAPK in the trigeminal ganglion. These results suggest that microglial cell activation in the MDH and p38 MAPK activation in the hyperactive microglial cells play an important role in the development of facial neuropathic pain following MNT. The results also suggest that ERK activation in the trigeminal ganglion contributes microglial cell activation and facial neuropathic pain.

Keywords

References

  1. Sweet WH: Deafferentation pain after posterior rhizotomy, trauma to a limb, and herpes zoster. Neurosurgery 1984;15:928-932
  2. Fields HL: Treatment of trigeminal neuralgia. N Engl J Med 1996;334:1125-1126 https://doi.org/10.1056/NEJM199604253341709
  3. Watkins LR, Maier SF: Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 2002;82:981-1011 https://doi.org/10.1152/physrev.00011.2002
  4. Watkins LR, Maier SF: Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2003;2:973-985 https://doi.org/10.1038/nrd1251
  5. 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 https://doi.org/10.1016/j.pain.2004.12.022
  6. 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 https://doi.org/10.1016/0006-8993(91)91729-K
  7. 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 https://doi.org/10.1006/exnr.1994.1165
  8. Fu KY, Light AR, Matsushima GK, Maixner W: Microglial reactions after subcutaneous formalin injection into the rat hind paw. Brain Res 1999;825:59-67 https://doi.org/10.1016/S0006-8993(99)01186-5
  9. Kalla R, Liu Z, Xu S, Koppius A, Imai Y, Kloss CU, et al: Microglia and the early phase of immune surveillance in the axotomized facial motor nucleus: impaired microglial activation and lymphocyte recruitment but no effect on neuronal survival or axonal regeneration in macrophage-colony stimulating factor-deficient mice. J Comp Neurol 2001;436:182-201 https://doi.org/10.1002/cne.1060
  10. 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 https://doi.org/10.1523/JNEUROSCI.23-10-04017.2003
  11. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, et al: P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 2003;424:778-783 https://doi.org/10.1038/nature01786
  12. 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 https://doi.org/10.1002/glia.10308
  13. Tsuda M, Inoue K, Salter MW: Neuropathic pain and spinal microglia: a big problem from molecules in 'small' glia. Trends Neurosci 2005;28:101-107 https://doi.org/10.1016/j.tins.2004.12.002
  14. Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, et al.: Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc Natl Acad Sci USA 2001;98:14669-14674 https://doi.org/10.1073/pnas.251341998
  15. Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J: Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci 2001;21:2580-2588 https://doi.org/10.1523/JNEUROSCI.21-08-02580.2001
  16. Tikka TM, Koistinaho JE: Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol 2001;166:7527-7533 https://doi.org/10.4049/jimmunol.166.12.7527
  17. Watkins LR, Milligan ED, Maier SF: Glial activation: a driving force for pathological pain. Trends Neurosci 2001;24:450-455 https://doi.org/10.1016/S0166-2236(00)01854-3
  18. Zimmermann M: Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983;16:109-110 https://doi.org/10.1016/0304-3959(83)90201-4
  19. Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J: Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 1998;95:15769- 15774
  20. Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, et al: Blockade of microglial activation is neuroprotective in the 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 2002;22:1763-1771 https://doi.org/10.1523/JNEUROSCI.22-05-01763.2002
  21. Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, Sarang S, et al: Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 2002; 417:74-78 https://doi.org/10.1038/417074a
  22. Raghavendra V, Tanga F, DeLeo JA: Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 2003;306:624-630 https://doi.org/10.1124/jpet.103.052407
  23. Zhang SC, Goetz BD, Duncan ID: Suppression of activated microglia promotes survival and function of transplanted oligodendroglial progenitors. Glia 2003;41:191-198 https://doi.org/10.1002/glia.10172
  24. Colburn RW, DeLeo JA, Rickman AJ, Yeager MP, Kwon P, Hickey WF: Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J Neuroimmunol 1997;79:163-175 https://doi.org/10.1016/S0165-5728(97)00119-7
  25. Kreutzberg GW: Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996;19:312-318 https://doi.org/10.1016/0166-2236(96)10049-7
  26. Sweitzer SM, Colburn RW, Rutkowski M, DeLeo JA: Acute peripheral inflammation induces moderate glial activation and spinal IL-1beta expression that correlates with pain behavior in the rat. Brain Res 1999;829:209-221 https://doi.org/10.1016/S0006-8993(99)01326-8
  27. Wieseler-Frank J, Maier SF, Watkins LR: Glial activation and pathological pain. Neurochem Int 2004;45:389-395 https://doi.org/10.1016/j.neuint.2003.09.009
  28. Obata K, Yamanaka H, Kobayashi K, Dai Y, Mizushima T, Katsura H, et al: Role of mitogen-activated 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 https://doi.org/10.1523/JNEUROSCI.3388-04.2004