Minocycline and fluorocitrate suppress spinal nociceptive signaling in intrathecal IL-1β-induced thermal hyperalgesic rats

Chun-Sung Sung, Chen-Hwan Cherng, Zhi-Hong Wen, Wen-Kuei Chang, Shi-Ying Huang, Shinn-Long Lin, Kwok-Hon Chan, Chih-Shung Wong
Glia 2012, 60 (12): 2004-17
We previously demonstrated that intrathecal IL-1β caused thermal hyperalgesia in rats. This study was conducted to examine the effects and cellular mechanisms of glial inhibitors on IL-1β-induced nociception in rats. The effects of minocycline (20 μg), fluorocitrate (1 nmol), and SB203580 (5 μg) on IL-1β (100 ng) treatment in rats were measured by nociceptive behaviors, western blotting of p38 mitogen-activated protein kinase (MAPK) and inducible nitric oxide synthase (iNOS) expression, cerebrospinal fluid nitric oxide (NO) levels, and immunohistochemical analyses. The results demonstrated that intrathecal IL-1β activated microglia and astrocytes, but not neurons, in the dorsal horn of the lumbar spinal cord, as evidenced by morphological changes and increased immunoreactivity, phosphorylated p38 (P-p38) MAPK, and iNOS expression; the activation of microglia and astrocytes peaked at 30 min and lasted for 6 h. The immunoreactivities of microglia and astrocytes were significantly increased at 30 min (6.6- and 2.7-fold, respectively) and 6 h (3.3- and 4.0-fold, respectively) following IL-1β injection, as compared with saline controls at 30 min (all P < 0.01). IL-1β induced P-p38 MAPK and iNOS expression predominantly in microglia and less in astrocytes. Minocycline, fluorocitrate, or SB203580 pretreatment suppressed this IL-1β-upregulated P-p38 MAPK mainly in microglia and iNOS mainly in astrocytes; minocycline exhibited the most potent effect. Minocycline and fluorocitrate pretreatment abrogated IL-1β-induced NO release and thermal hyperalgesia in rats. In conclusion, minocycline, fluorocitrate, and SB203580 effectively suppressed the IL-1β-induced central sensitization and hyperalgesia in rats.

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