Minocycline Effects on IL-6 Concentration in Macrophage and Microglial Cells in a Rat Model of Neuropathic Pain (original) (raw)
Related papers
Iranian journal of basic medical sciences, 2018
Several lines of evidence showed that minocycline possesses antioxidant and anti-inflammatory properties. This study aimed to demonstrate the effects of minocycline in rats subjected to chronic constriction injury (CCI). In this study four groups (n = 6-8) of rats were used as follows: Sham, CCI, CCI + minocycline (MIN) 10 mg/Kg (IP) and CCI + MIN 30 mg/Kg (IP). On days 3, 7, 14, and 21 post-surgery hot-plate, acetone, and von Frey tests were carried out. Finally, Motor Nerve Conduction Velocity Evaluation (MNCV) assessment was performed and spinal cords were harvested in order to measure tissue concentrations of TNF_α, IL-1β, Glutathione peroxidase (GPx), Superoxide dismutase (SOD) and Malondialdehyde (MDA). Extent of perineural inflammation and damage around the sciatic nerve was histopathologically evaluated. Our results demonstrated that CCI significantly caused hyperalgesia and allodynia twenty-one days after CCI. MIN attenuated heat hyperalgesia, cold and mechanical allodynia ...
Journal of Neuroimmunology, 2014
In neuropathic pain the repeated minocycline treatment inhibited the mRNA and protein expression of the microglial markers and metalloproteinase-9 (MMP-9). The minocycline diminished the pronociceptive (IL-6, IL-18), but not antinociceptive (IL-1alpha, IL-4, IL-10) cytokines at the spinal cord level. In vitro primary cell culture studies have shown that MMP-9, TIMP-1, IL-1beta, IL-1alpha, IL-6, IL-10, and IL-18 are of microglial origin. Minocycline reduces the production of pronociceptive factors, resulting in a more potent antinociceptive effect. This change in the ratio between pro-and antinociceptive factors, in favour of the latter may be the mechanism of minocycline analgesia in neuropathy.
Systemic administration of minocycline inhibits formalin-induced inflammatory pain in rat
Brain Research, 2006
It has been demonstrated that spinal microglial activation is involved in formalin-induced pain and that minocycline, an inhibitor of microglial activation, attenuate behavioral hypersensitivity in neuropathic pain models. We investigated whether minocycline could have any anti-nociceptive effect on inflammatory pain, after intraperitonial administration of minocycline, 1 h before formalin (5%, 50 μl) injection into the plantar surface of rat hindpaw. Minocycline (15, 30, and 45 mg/kg) significantly decreased formalin-induced nociceptive behavior during phase II, but not during phase I. The enhancement in the number of c-Fos-positive cells in the L4-5 spinal dorsal horn (DH) and the magnitude of paw edema induced by formalin injection during phase II were significantly reduced by minocycline. Minocycline inhibited synaptic currents of substantia gelatinosa (SG) neurons in the spinal DH, whereas membrane electrical properties of dorsal root ganglion neurons were not affected by minocycline. Analysis with OX-42 antibody revealed the inhibitory effect of minocycline on microglial activation 3 days after formalin injection.
Neuroscience, 2010
A role of neuropeptides in neuropathic pain development has been implicated; however, the neuroimmune interactions that are involved in the underlying mechanisms may be more important than previously thought. To examine a potential role of relations between glia cells and neuropeptides in neuropathic pain, we performed competitive reverse-transcription polymerase chain reaction (RT-PCR) from the dorsal lumbar spinal cord and the dorsal root ganglion (DRG) after chronic constriction injury (CCI) in the rat sciatic nerve. The RT-PCR results indicated that complement component 1, q subcomponent (C1q) mRNA expression was higher than glial fibrillary acidic protein (GFAP) in the spinal cord 3 and 7 days post-CCI, suggesting that spinal microglia and perivascular macrophages are more activated than astrocytes. In parallel, we observed a strong upregulation of prodynorphin mRNA in the spinal cord after CCI, with no changes in the expression of proenkephalin or pronociceptin. Conversely, the expression of GFAP mRNA in the DRG was higher than C1q, which suggests that the satellite cells are activated shortly after injury, followed by the macrophages and polymorphonuclear leukocytes infiltrating the DRG. In the DRG, we also observed a very strong upregulation of prodynorphin (1387%) as well as pronociceptin (122%) and a downregulation of proenkephalin (47%) mRNAs. Interestingly, preemptive and repeated i.p. injection of minocycline reversed the activation of microglia/macrophages in the spinal cord and the trafficking of peripheral immune cells into the DRG, and markedly diminished the upregulation of prodynorphin and pronociceptin in the DRG. We thus provide novel findings that inhibition of C1q-positive cells by minocycline can diminish injury-induced neuropeptide changes in the DRG. This suggests that immune cells-derived pronociceptive factors may influence opioid peptide expression. Therefore, the injuryinduced activation of microglia and leukocytes and the subsequent activation of neuropeptides involved in nociception processes are potential targets for the attenuation of neuropathic pain.
It is confirmed that pharmacological attenuation of glial cells can alleviate neuropathic pain by lowering proinflammatory cytokine expression. The present study tries to confirm that post-injury administration of glia inhibitor, minocycline, can attenuate the neuropathic pain symptoms and improves the efficacy of morphine anti-nociception in chronic constriction injury (CCI). Male Wistar rats (230–270 g) underwent surgery for induction CCI model of neuropathy. For assessment of the thermal hyperalgesia and mechanical allodynia after CCI induction, morphine (2.5, 5, 7.5, 10 and 15 mg/kg; s.c.) and saline were administered on post-operative days (PODs) 0, 6 and 14. Hargreaves and Von–Frey tests were performed before and 30 min after morphine administration , respectively. The results showed significant decrease in antinociceptive effect of morphine on POD 6 compared to POD 0 only at the dose of 5 mg/kg. On the other hand, on POD 14 the antinociceptive effect of morphine (5, 7.5, 10 and 15 mg/kg) significantly decreased in comparison with POD 0. In another set of experiments, animals received minocycline (10, 20 and 40 mg/kg; i.p.) for eight days from POD 6 to 13 and then the antinociceptive effect of single dose of morphine 5 mg/kg was tested on POD 14. Behavioral tests showed that minocycline (40 mg/kg) could effectively attenuate the thermal hyperalgesia and mechanical allodynia on POD 13. Moreover, minocycline (40, 20 mg/kg) improved the anti-hyperalgesic, and minocycline (40 mg/kg) improved the anti-allodynic effects of morphine 5 mg/kg on POD 14. It seems that the reduction of antinociceptive effect of morphine after CCI may be mediated through glia activation. Modulation of glial activity by minocycline can attenuate CCI-induced neuropathic pain. It is also shown that repeated post-injury administration of minocycline improves the antinociceptive effect of morphine in neuropathic pain.
Research in pharmaceutical sciences
Glutamate neurotoxicity and pro-inflammatory cytokines have an important role in the central sensitization of neuropathic pain. The purpose of the present study was to evaluate anti-hyperalgesic effect of repeated administration of ceftriaxone, which selectively activates and increases the expression of glutamate transporter, as well as minocycline, a selective inhibitor of microglia activation, either alone or together in Wistar rats subjected to the chronic constriction injury (CCI) of sciatic nerve. Ceftriaxone (100, 150 and 200 mg/kg) and minocycline (25, 50 and 100 mg/kg) were administered intraperitoneally from the day of surgery for seven consecutive days. Thermal hyperalgesia was assessed by focal radiant heat source on the hind paw of animals one day before surgery and on 3, 5, 7, 10 and 14 days following that. Ceftriaxone dose dependently, attenuated thermal hyperalgesia in animals. None of the administered doses of minocycline affected the CCI induced-thermal hyperalgesia...
European Journal of Neuroscience, 2005
Activation of p38 mitogen-activated protein kinase (p38) in spinal microglia is implicated in spinal nociceptive processing. Minocycline, a tetracycline derivative, displays selective inhibition of microglial activation, a function that is distinct from its antibiotic activity. In the present study we examined antinociceptive effects of intrathecal (IT) administration of minocycline in experimental models of inflammation-evoked hyperalgesia in addition to the effect of minocycline on stimulation-induced activation of p38 in spinal microglia. Intrathecal minocycline produced a dose-dependent reduction of formalin-evoked second-phase flinching behaviour in rats, and prevented thermal hyperalgesia induced by carrageenan injection into the paw. In contrast, systemic delivery (intraperitoneally) of minocycline inhibited the first but not the second phase of formalin-induced flinching, and it had no effect on carrageenan-induced hyperalgesia. Centrally mediated hyperalgesia induced by IT delivery of N-methyl-d-aspartate was completely blocked by IT minocycline. An increase in phosphorylation (activation) of p38 (P-p38) was observed in the dorsal spinal cord after carrageenan paw injection, assessed by both Western blotting and immunohistochemistry. The increased P-p38 immunoreactivity was seen primarily in microglia but also in a small population of neurons. Minocycline, at the IT dose that blocked carrageenaninduced hyperalgesia, also attenuated the increased P-p38 in microglia. In addition, minocycline suppressed lipopolysaccharideevoked P-p38 in cultured spinal microglial cells. Taken together, these findings show that minocycline given IT produces a potent and consistent antinociception in models of tissue injury and inflammation-evoked pain, and they provide strong support for the idea that this effect is mediated by direct inhibition of spinal microglia and subsequent activation of p38 in these cells.