title: Minocycline and fluorocitrate suppress spinal nociceptive signaling in intrathecal IL-1β-induced thermal hyperalgesic rats.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Chun-Sung
authors.initials: CS
authors.lastname: Sung
authors.forename: Chen-Hwan
authors.initials: CH
authors.lastname: Cherng
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Wen
authors.forename: Wen-Kuei
authors.initials: WK
authors.lastname: Chang
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Huang
authors.forename: Shinn-Long
authors.initials: SL
authors.lastname: Lin
authors.forename: Kwok-Hon
authors.initials: KH
authors.lastname: Chan
authors.forename: Chih-Shung
authors.initials: CS
authors.lastname: Wong
mesh_terms: D000818:Animals; D002951:Citrates / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007278:Injections, Spinal; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008297:Male; D008911:Minocycline / Q000627:therapeutic use*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D002951:Citrates; D053583:Interleukin-1beta; C007744:fluorocitrate; D008911:Minocycline