Minocycline blocks lipopolysaccharide induced hyperalgesia by suppression of microglia but not astrocytes

Abstract

Systemic injection of lipopolysaccharide (LPS) induces a robust immune response as well as thermal and mechanical hyperalgesia. Spinal and peripheral glial cells have been implicated as important mediators in this hyperalgesia but the specific contributions of microglia versus astrocytes are not entirely clear. To better define these mechanisms, this study examined the febrile response, nociceptive sensitivity, glial cell reactivity and cytokine production in the dorsal root ganglion (DRG) and spinal cord in rats following systemic treatment with LPS and the effects of minocycline in countering these responses. Intraperitoneal LPS injection resulted in an increase in core body temperature and produced hyperalgesia to heat and mechanical stimuli. Western blot studies revealed increased expression of microgial cell, macrophage and satellite cell markers in DRG and microglial and astrocyte markers in spinal cord following LPS treatment. Real-time RT-PCR indicated that LPS treatment increased cytokine mRNA expression levels in both the DRG and the spinal cord. Minocycline suppressed all LPS-induced behavioral effects but not the febrile response. Moreover, minocycline prevented LPS induced microglia/macrophage activation and cytokine responses in spinal cord and DRG, but did not affect the activation of astrocytes/satellite cells. These data demonstrate that LPS-induced changes in nociceptive sensitivity are likely mediated by activation of microglial cells and/or macrophages in the spinal cord and DRG.

Lipopolysaccharide-Induced Apoptosis of Astrocytes: Therapeutic Intervention by Minocycline

“…The results are in line with the studies stating that minocycline was ineffective in dampening the astrocytic activation (Tikka et al 2001;Yoon et al 2012;Haber et al 2013). Matsukawa et al (2009) were also reported that low-dose minocycline was protective to neurons in both in vivo and in vitro experimental models of stroke, while it provided no protection to astrocytes in the same models.…”

Minocycline modulates neuropathic pain behaviour and cortical M1–M2 microglial gene expression in a rat model of depression

“…Neither acute nor chronic minocycline administration altered basal mechanical thresholds of either sham or OB rats. Similarly, studies have demonstrated that acute (Mika et al, 2009), repeated (3 days) (Yoon et al, 2012), or chronic (Guasti et al, 2009) minocycline administration does not alter nociceptive responding to mechanical stimuli in the absence of a noxious insult/nerve injury. Thus, microglial activation may not underlie the OB-related increase in nociceptive responding to sensory stimuli (prior to SNL), indicating a dissociation between depressive-like behaviour and allodynia in the absence of nerve injury.…”

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

“…Concomitant systemic treatment with a pharmacological modulator of glial activation such as ibudilast, which functions as a nonselective phosphodiesterase inhibitor but has broad effects on glial function (Gibson et al, 2006), is effective at preventing CD11b and GFAP induction by morphine ), a result replicated by targeted intra-NAc infusions of ibudilast (Schwarz et al, 2011). Minocycline, a highly lipidsoluble tetracycline antibiotic that can also modulate glial activity, is capable of preventing LPS-induced upregulation of microglial Iba1 but has no effect on astrocytic GFAP upregulation following LPS (Yoon et al, 2012). In vitro assessment of cultured rat microglia confirms that minocycline can inhibit microglial activation to morphine, measured by a dose-dependent reduction in morphineinduced cyclooxygenase-1 production following minocycline treatment (Hutchinson et al, 2008).…”