scholarly journals Minocycline Enhances the Effectiveness of Nociceptin/Orphanin FQ during Neuropathic Pain

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Katarzyna Popiolek-Barczyk ◽  
Ewelina Rojewska ◽  
Agnieszka M. Jurga ◽  
Wioletta Makuch ◽  
Ferenz Zador ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Cell Activation ◽  
Microglial Cell ◽  
Lumbar Spinal Cord ◽  
Orphanin Fq ◽  
Binding Assays ◽  
Analgesic Effects ◽  
Primary Microglial Cell ◽  
Lumbar Spinal

Nociceptin/orphanin FQ (N/OFQ) antinociception, which is mediated selectively by the N/OFQ peptide receptor (NOP), was demonstrated in pain models. In this study, we determine the role of activated microglia on the analgesic effects of N/OFQ in a rat model of neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve. Repeated 7-day administration of minocycline (30 mg/kg i.p.), a drug that affects microglial activation, significantly reduced pain in CCI-exposed rats and it potentiates the analgesic effects of administered N/OFQ (2.5–5 μg i.t.). Minocycline also downregulates the nerve injury-induced upregulation of NOP protein in the dorsal lumbar spinal cord. Ourin vitrostudy showed that minocycline reducedNOPmRNA, but not protein, level in rat primary microglial cell cultures. In [35S]GTPγS binding assays we have shown that minocycline increases the spinal N/OFQ-stimulated NOP signaling. We suggest that the modulation of the N/OFQ system by minocycline is due to the potentiation of its neuronal antinociceptive activity and weakening of the microglial cell activation. This effect is beneficial for pain relief, and these results suggest new targets for the development of drugs that are effective against neuropathic pain.

scholarly journals Biphalin, a Dimeric Enkephalin, Alleviates LPS-Induced Activation in Rat Primary Microglial Cultures in Opioid Receptor-Dependent and Receptor-Independent Manners

2017 ◽  
Vol 2017 ◽  
pp. 1-19 ◽  
Author(s):  
Katarzyna Popiolek-Barczyk ◽  
Anna Piotrowska ◽  
Wioletta Makuch ◽  
Joanna Mika
Keyword(s):  
Neuropathic Pain ◽  
Opioid Receptor ◽  
Pain Therapy ◽  
Cell Activation ◽  
Microglial Cell ◽  
Preclinical Model ◽  
No Production ◽  
Dependent Manner ◽  
Analgesic Effects ◽  
Primary Microglial Cell

Neuropathic pain is relatively less responsive to opioids than other types of pain, which is possibly due to a disrupted opioid system partially caused by the profound microglial cell activation that underlines neuroinflammation. We demonstrated that intrathecally injected biphalin, a dimeric enkephalin analog, diminished symptoms of neuropathy in a preclinical model of neuropathic pain in rats (CCI, chronic constriction injury of the sciatic nerve) at day 12 postinjury. Using primary microglial cell cultures, we revealed that biphalin did not influence cell viability but diminished NO production and expression of Iba1 in LPS-stimulated cells. Biphalin also diminished MOP receptor level, as well as pronociceptive mediators (iNOS, IL-1β, and IL-18) in an opioid receptor-dependent manner, and it was correlated with diminished p-NF-κB, p-IκB, p-p38MAPK, and TRIF levels. Biphalin reduced IL-6, IL-10, TNFα, p-STAT3, and p-ERK1/2 and upregulated SOCS3, TLR4, and MyD88; however, this effect was not reversed by naloxone pretreatment. Our study provides evidence that biphalin diminishes neuropathy symptoms, which might be partially related to reduced pronociceptive mediators released by activated microglia. Biphalin may be a putative drug for future pain therapy, especially for the treatment of neuropathic pain, when the lower analgesic effects of morphine are correlated with profound microglial cell activation.

scholarly journals Attenuation of oxidative stress, inflammation and apoptosis by ethanolic and aqueous extracts of Crocus sativus L. stigma after chronic constriction injury of rats

2014 ◽  
Vol 86 (4) ◽  
pp. 1821-1832 ◽  
Author(s):  
BAHAREH AMIN ◽  
KHALIL ABNOUS ◽  
VAHIDEH MOTAMEDSHARIATY ◽  
HOSSEIN HOSSEINZADEH
Keyword(s):  
Oxidative Stress ◽  
Neuropathic Pain ◽  
Proinflammatory Cytokines ◽  
Chronic Constriction Injury ◽  
Crocus Sativus ◽  
Lumbar Spinal Cord ◽  
Aqueous Extracts ◽  
Apoptotic Pathways ◽  
Factor Α ◽  
Lumbar Spinal

In our previous study, the ethanolic and aqueous extracts of Crocus sativus elicited antinociceptive effects in the chronic constriction injury (CCI) model of neuropathic pain. In this study, we explored anti-inflammatory, anti-oxidant and anti-apoptotic effects of such extracts in CCI animals. A total of 72 animals were divided as vehicle-treated CCI rats, sham group, CCI animals treated with the effective dose of aqueous and ethanolic extracts (200 mg/kg, i.p.). The lumbar spinal cord levels of proinflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin 6 (IL-6), were evaluated at days 3 and 7 after CCI (n=3, for each group). The apoptotic protein changes were evaluated at days 3 and 7 by western blotting. Oxidative stress markers including malondialdehyde (MDA) and glutathione reduced (GSH), were measured on day 7 after CCI. Inflammatory cytokines levels increased in CCI animals on days 3 and 7, which were suppressed by both extracts. The ratio of Bax/ Bcl2 was elevated on day 3 but not on day 7, in CCI animals as compared to sham operated animals and decreased following treatment with both extracts at this time. Both extracts attenuated MDA and increased GSH levels in CCI animals. It may be concluded that saffron alleviates neuropathic pain, at least in part, through attenuation of proinflammatory cytokines, antioxidant activity and apoptotic pathways.

scholarly journals Melanocortin 4 Receptor Mediates Neuropathic Pain Through p38MAPK in Spinal Cord

2012 ◽  
Vol 39 (4) ◽  
pp. 458-464 ◽  
Author(s):  
Haichen Chu ◽  
Jiangling Xia ◽  
Hongmei Xu ◽  
Zhao Yang ◽  
Jie Gao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Time Course ◽  
Lumbar Spinal Cord ◽  
Enzyme Linked Immunosorbent Assay ◽  
Melanocortin 4 Receptor ◽  
Male Wistar Rats ◽  
Underlying Mechanisms ◽  
Lumbar Spinal ◽  
Somatosensory Nervous System

Background:Neuropathic pain is characterised by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli. Neuropathic pain develops as a result of lesions or disease affecting the somatosensory nervous system either in the periphery or centrally. Melanocortin 4 receptor (MC4R) plays an important role in the initiation of neuropathic pain but the underlying mechanisms are still unclear.Methods:Adult male Wistar rats were given chronic constriction injury (CCI) or sham operations. Part of CCI rats were intrathecally treated with HS014 (MC4R antagonist) or SB203580 (p38MAPK inhibitor). On the third, seventh and fourteenth day, the thermal threshold of operated paws was tested. In addition, the MC4R or phosphorylated p38MAPK (p-p38MAPK) levels of lumbar spinal cord were tested with ELISA (enzyme-linked immunosorbent assay), western blot and immunohistochemistry.Results:Here we demonstrate that (1) both HS014 and SB203580 reduced CCI reduced hyperalgesia (2) p-p38MAPK was increased after CCI with a time course parallel to that of the MC4R change, (3) The p38 activation was prevented by blocking MC4R with an antagonist HS014, but MC4R-IR was not prevented by SB203580. (4) MC4R and p-p38MAPK were located in the same cells.Conclusion:The mechanisms of neuropathic pain mediated by MC4R is related to the inhibition of p38MAPK activation. P38MAPK may be a downstream of MC4R.

scholarly journals Alterations in the Anandamide Metabolism in the Development of Neuropathic Pain

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Natalia Malek ◽  
Mateusz Kucharczyk ◽  
Katarzyna Starowicz
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Mrna Level ◽  
Inhibitory Effect ◽  
Lumbar Spinal Cord ◽  
Local Synthesis ◽  
Time Points ◽  
Pain Pathways ◽  
Lumbar Spinal ◽  
Synthesis And Degradation

Endocannabinoids (EC), particularly anandamide (AEA), released constitutively in pain pathways might be accountable for the inhibitory effect on nociceptors. Pathogenesis of neuropathic pain may reflect complex remodeling of the dorsal root ganglia (DRGs) and spinal cord EC system. Multiple pathways involved both in the biosynthesis and degradation of AEA have been suggested. We investigated the local synthesis and degradation features of AEA in DRGs and spinal cord during the development and maintenance of pain in a model of chronic constriction injury (CCI). All AEA synthesis and degradation enzymes are present on the mRNA level in DRGs and lumbar spinal cord of intact as well as CCI-treated animals. Deregulation of EC system components was consistent with development of pain phenotype at days 3, 7, and 14 after CCI. The expression levels of enzymes involved in AEA degradation was significantly upregulated ipsilateral in DRGs and spinal cord at different time points. Expression of enzymes of the alternative, sPLA2-dependent and PLC-dependent, AEA synthesis pathways was elevated in both of the analyzed structures at all time points. Our data have shown an alteration of alternative AEA synthesis and degradation pathways, which might contribute to the variation of AEA levels and neuropathic pain development.

Microglial Inhibition Influences XCL1/XCR1 Expression and Causes Analgesic Effects in a Mouse Model of Diabetic Neuropathy

2016 ◽  
Vol 125 (3) ◽  
pp. 573-589 ◽  
Author(s):  
Magdalena Zychowska ◽  
Ewelina Rojewska ◽  
Anna Piotrowska ◽  
Grzegorz Kreiner ◽  
Joanna Mika
Keyword(s):  
Neuropathic Pain ◽  
Diabetic Neuropathy ◽  
Cell Cultures ◽  
Neutralizing Antibody ◽  
Diabetic Neuropathic Pain ◽  
Nociceptive Transmission ◽  
Analgesic Effects ◽  
Primary Microglial Cell ◽  
Neuropathic Pain Model ◽  
Streptozotocin Induced Diabetes

Abstract Background Recent studies indicated the involvement of some chemokines in the development of diabetic neuropathy; however, participation of the chemokine-C-motif ligand (XCL) subfamily remains unknown. The goal of this study was to examine how microglial inhibition by minocycline hydrochloride (MC) influences chemokine-C-motif ligand 1 (XCL1)–chemokine-C-motif receptor 1 (XCR1)/G protein–coupled receptor 5 expression and the development of allodynia/hyperalgesia in streptozotocin-induced diabetic neuropathy. Methods The studies were performed on streptozotocin (200 mg/kg, intraperitoneally)-induced mouse diabetic neuropathic pain model and primary glial cell cultures. The MC (30 mg/kg, intraperitoneally) was injected two times daily until day 21. XCL1 and its neutralizing antibody were injected intrathecally, and behavior was evaluated with von Frey and cold plate tests. Quantitative analysis of protein expression of glial markers, XCL1, and/or XCR1 was performed by Western blot and visualized by immunofluorescence. Results MC treatment diminished allodynia (0.9 ± 0.1 g; n = 7 vs. 3.8 ± 0.7 g; n = 7) and hyperalgesia (6.5 ± 0.6 s; n = 7 vs. 16.5 ± 1 s; n = 7) in the streptozotocin-induced diabetes. Repeated MC administration prevented microglial activation and inhibited the up-regulation of the XCL1/XCR1 levels. XCL1 administration (10 to 500 ng/5 μl; n = 9) in naive mice enhanced nociceptive transmission, and injections of neutralizing XCL1 (4 to 8 μg/5 μl; n = 10) antibody into the mice with diabetic neuropathic pain diminished allodynia/hyperalgesia. Microglia activation evoked in primary microglial cell cultures resulted in enhanced XCL1 release and XCR1 expression. Additionally, double immunofluorescence indicated the widespread coexpression of XCR1-expressing cells with spinal neurons. Conclusions In diabetic neuropathy, declining levels of XCL1 evoked by microglia inhibition result in the cause of analgesia. The putative mechanism corroborating this finding can be related to lower spinal expression of XCR1 together with the lack of stimulation of these XCR1 receptors, which are localized on neurons.

scholarly journals Long Noncoding RNA Expression Profile in BV2 Microglial Cells Exposed to Lipopolysaccharide

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Yajuan Li ◽  
Qingmin Li ◽  
Cunjuan Wang ◽  
Shengde Li ◽  
Lingzhi Yu
Keyword(s):  
Neuropathic Pain ◽  
Signaling Pathway ◽  
Noncoding Rna ◽  
Cell Activation ◽  
Differentially Expressed ◽  
Microglial Cells ◽  
Receptor Signaling ◽  
Microglia Cell ◽  
Receptor Signaling Pathway

Neuropathic pain, which is one of the most common forms of chronic pain, seriously increases healthcare costs and impairs patients’ quality of life with an incidence of 7–10% worldwide. Microglia cell activation plays a key role in the progression of neuropathic pain. Better understanding of novel molecules modulating microglia cell activation and these underlying functions will extremely benefit the exploration of new treatment. Recent studies suggested long noncoding RNAs may be involved in neuropathic pain. However, its underlying functions and mechanisms in microglia cell activation remain unclear. To identify the differentially expressed lncRNAs and predict their functions in the progression of microglia cell activation, GSE103156 was analyzed using integrated bioinformatics methods. The expression levels of selected lncRNAs and mRNAs were determined by real-time PCR. In the present study, a total of 56 lncRNAs and 298 mRNAs were significantly differentially expressed. The differentially expressed mRNAs were mainly enriched in NF-kappa B signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway, and NOD-like receptor signaling pathway. The top 10 hub genes were Tnf, Il6, Stat1, Cxcl10, Il1b, Tlr2, Irf1, Ccl2, Irf7, and Ccl5 in the PPI network. Our results showed that Gm8989, Gm8979, and AV051173 may be involved in the progression of microglia cell activation. Taken together, our findings suggest that lots of lncRNAs may be involved in BV2 microglia cell activation in vitro. The findings may provide relevant information for the development of promising targets for the microglial cells activation of neuropathic pain in vivo in the future.

scholarly journals Cancer pain and neuropathic pain are associated with Aβ sensory neuronal plasticity in dorsal root ganglia and abnormal sprouting in lumbar spinal cord

2018 ◽  
Vol 14 ◽  
pp. 174480691881009 ◽  
Author(s):  
Yong Fang Zhu ◽  
Jacek M Kwiecien ◽  
Wojciech Dabrowski ◽  
Robert Ungard ◽  
Kan Lun Zhu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Cancer Pain ◽  
Dorsal Root Ganglia ◽  
Neuronal Plasticity ◽  
Dorsal Root ◽  
Lumbar Spinal Cord ◽  
Lumbar Spinal

31. Therapeutic morphine prolongs neuropathic pain in rats: A role for TLR4 and inflammasome signaling in the lumbar spinal cord

2014 ◽  
Vol 40 ◽  
pp. e9-e10
Author(s):  
P.M. Grace ◽  
K.A. Strand ◽  
E.L. Galer ◽  
Y. Zhang ◽  
D. Berkelhammer ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Lumbar Spinal Cord ◽  
Lumbar Spinal
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