Journal of molecular neuroscience : MN
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Neuropathic pain is characterized by hyperalgesia, allodynia, and spontaneous pain. Recent studies have shown that glycoprotein nonmetastatic melanoma B (GPNMB) plays a pivotal role in neuronal survival and neuroprotection. However, the role of GPNMB in neuropathic pain remains unknown. ⋯ Furthermore, the intrathecal injection of siRNA1-GPNMB inhibited the expression of GPNMB and pro-inflammatory factors (TNF-α, IL-1β, and IL-6) and alleviated mechanical allodynia and thermal hyperalgesia in the chronic constriction injury (CCI) model of rats. Taken together, our findings suggest that siRNA against GPNMB can alleviate the chronic neuropathic pain caused by CCI, and this effect may be mediated by attenuated expression of TNF-α, IL-1β, and IL-6 in the spinal cord of CCI rats. Therefore, inhibition of GPNMB may provide a novel strategy for the treatment of neuropathic pain.
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After spinal cord injury (SCI), the level of adenosine triphosphate (ATP) and extracellular matrix (ECM) is increased. Formation of the glial scar is a complex process that is primarily attributed to astrocytic proliferation, and the fibrotic scar results from ECM deposition. In our previous researches, ATP and fibronectin was able to separately stimulate the proliferation of astrocytes. ⋯ In the present study, we discovered that ATP was able to increase the expression of Sox2 and Sox9; fibronectin did not have this direct function. Sox9 was only involved in the proliferation increased by ATP, and Sox2 influenced the release of IL-6 stimulated by ATP. Understanding the critical role of Sox2 and Sox9 mediated by ATP may provide a potential target for therapeutic intervention in spinal cord injury.
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In the present study, we investigated the anti-inflammatory mechanisms by which gabapentin enhances morphine anti-nociceptive effect in neuropathic pain in rats and the interaction between the anti-nociceptive effects of gabapentin on morphine and the interleukin (IL)-10-heme-oxygenase (HO)-1 signal pathway in a rat model of neuropathic pain. The neuropathic pain model was induced via a left L5/6 spinal nerve ligation (SNL) in rats. The anti-nociceptive effect of gabapentin and IL-10 on morphine was examined over a 7-day period, and the effects of the anti-IL-10 and HO-1 inhibitor zinc protoporphyrin (ZnPP) on gabapentin/morphine co-injection were assessed. ⋯ Gabapentin attenuated morphine tolerance over 7 days of co-administration, and reduced the expression of pro-inflammatory cytokines but increased IL-10 and HO-1 expression. The effect of gabapentin on morphine was partially blocked using the anti-IL-10 antibody or the HO-1 inhibitor zinc protoporphyrin. Our findings indicated that the anti-nociceptive effects of gabapentin on morphine might be caused by activation of the IL-10-HO-1 signalling pathway, which resulted in the inhibition of the expression of pro-inflammatory cytokines in neuropathic pain in the rat spinal cord.
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Recent studies showed that combination of mu opioid receptor (MOP) agonism and monoamine reuptake inhibition may improve the therapeutic effect of opioids by reducing requirement for MOP activation. Tapentadol, showing such a combined mechanism of action, exhibits delayed analgesic tolerance development compared to pure MOP agonists. Here we investigated how opioid receptors are regulated following different schedules (two ranges of concentrations for 24 and 48 h) of tapentadol exposure in vitro in SH-SY5Y cells. ⋯ Differently from DAMGO, tapentadol or morphine showed no effects on MOP internalization. This study suggests that tapentadol affects MOP and NOP gene expression and MOP internalization showing a pattern distinct from classical MOP agonists. Whether these differences can explain the improved therapeutic profile of tapentadol remains to be investigated.
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Endoplasmic reticulum (ER) stress may play a role in status epilepticus (SE). Sprague-Dawley rats were randomized into three groups: control (saline), SE (pentylenetetrazol), and dentate gyrus (DG), pretreated with 2-deoxy-D-glucose (2-DG). Expression levels of glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), eukaryotic initiation factor 2α (eIF2α), and protein kinase RNA-like ER kinase (PERK) were determined. ⋯ GRP messenger RNA expression levels and protein levels in SE group was significantly increased as compared to the control group (P < 0.0001) and significantly decreased in DG group as compared to the SE group (P < 0.0001). Phosphorylated PERK protein expression level in SE group was significantly increased as compared to the control group (P < 0.0001), and significantly decreased in DG group as compared to the SE group (P < 0.0001) at the time of 12 and 24 h. Our results suggest that brain injury from SE might involve ER stress via the pro-apoptotic PERK-eIF2α-CHOP signaling pathway.