Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury.
Glial activation is known to contribute to pain hypersensitivity following spinal sensory nerve injury. In this study, we investigated mechanisms by which glial cell activation in medullary dorsal horn (MDH) would contribute to tactile hypersensitivity following inferior alveolar nerve and mental nerve transection (IAMNT). Activation of microglia and astrocytes was monitored at 2 h, 1, 3, 7, 14, 28, and 60 days using immunohistochemical analysis with OX-42 and GFAP antibodies, respectively. Tactile hypersensitivity was significantly increased at 1 day, and this lasted for 28 days after IAMNT. Microglial activation, primarily observed in the superficial laminae of MDH, was initiated at 1 day, maximal at 3 days, and maintained until 14 days after IAMNT. Astrocytic activation was delayed compared to that of microglia, being more profound at 7 and 14 days than at 3 days after IAMNT. Both tactile hypersensitivity and glial activation appeared to gradually reduce and then return to the basal level by 60 days after IAMNT. There was no significant loss of trigeminal ganglion neurons by 28 days following IAMNT, suggesting that degenerative changes in central terminals of primary afferents might not contribute to glial activation. Minocycline, an inhibitor of microglial activation, reduced microglial activation, inhibited p38 mitogen-activated protein kinase (MAPK) activation in microglia, and significantly attenuated the development of pain hypersensitivity in this model. These results suggest that glial activation in MDH plays an important role in the development of neuropathic pain and activation of p38 MAPK in hyperactive microglia contributes to pain hypersensitivity in IAMNT model.
Department of Physiology, College of Dentistry and Dental Research Institute, Seoul National University, Seoul 110-749, Republic of Korea Program in Molecular and Cellular Neuroscience, College of Dentistry and Dental Research Institute, Seoul National University, Seoul 110-749, Republic of Korea.
Zheng Gen
ZG
Piao
Ik-Hyun
IH
Cho
Chul Kyu
CK
Park
Jin Pyo
JP
Hong
Se-Young
SY
Choi
Sung Joong
SJ
Lee
Seungbok
S
Lee
Kyungpyo
K
Park
Joong Soo
JS
Kim
Seog Bae
SB
Oh
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D039481:CD11b Antigen; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology; D009475:Neurons, Afferent / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014275:Trigeminal Caudal Nucleus / Q000166:cytology / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000473:pathology / Q000503:physiopathology; D014276:Trigeminal Nerve / Q000503:physiopathology; D020433:Trigeminal Nerve Diseases / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D061221:Trigeminal Nerve Injuries; D015854:Up-Regulation / Q000502:physiology; D014855:Wallerian Degeneration / Q000473:pathology / Q000503:physiopathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D015415:Biomarkers; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; C509295:ITGAM protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D008911:Minocycline