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.

Hyperexcitability in Spinal WDR Neurons following Experimental Disc Herniation Is Associated with Upregulation of Fractalkine and Its Receptor in Nucleus Pulposus and the Dorsal Root Ganglion

“…In accordance with the earlier observation that microglial inhibition may prevent hyperalgesia [16, 17, 31], minocycline attenuated the increase in nociceptive signaling induced by NP in the present study. Data from earlier in vitro studies also suggest that inhibition of MAPK p38 in human NP cells inhibits inflammation [14].…”

The use of the antimicrobial peptide piscidin (PCD)-1 as a novel anti-nociceptive agent

“…The induction of iNOS in microglia, astrocytes, and neuronal cells in the spinal cord correlates with thermal hyperalgesia [58]. Here, we show that LPS- Fig.…”

Astrocytes, but not microglia, are activated in oxaliplatin and bortezomib-induced peripheral neuropathy in the rat

“…This possibility is further supported by the prevention of the observed astrogliosis by co-administration of minocycline, which has anti-inflammatory properties and has been shown to prevent the upregulation of proinflammatory cytokines in other models (Ledeboer et al, 2005; Mao-Ying et al, 2012). It is worth mentioning that some studies claim that minocycline is specific to microglia and has no effect on astrocyte activation (Yrjänheikki et al, 1999), whereas others show inhibition of both astrocytic and microglial activation (Ledeboer et al, 2005; Ryu et al, 2004; Sung et al, 2012; Teng et al, 2004). The findings of the current study are in support of the latter, which may be a model-dependent finding.…”

“…Like other tetracyclines, minocycline is frequently evaluated as an antibiotic, but the primary clinical use of minocycline since its FDA approval has been in the treatment of inflammatory acne vulgaris (Garner et al, 2012). Cytokines of interest for future studies in CIPN may include IL-1β and TNF-α (Sung et al, 2012; Mao-Ying et al, 2012) among others, although these are not specific to astrocytes.…”