scholarly journals NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Meng Liu ◽  
Su-Bo Zhang ◽  
Yu-Xuan Luo ◽  
Yan-Ling Yang ◽  
Xiang-Zhong Zhang ◽  
...  
Keyword(s):  
Binding Site ◽  
Dorsal Horn ◽  
Mechanical Allodynia ◽  
Spinal Dorsal Horn ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Painful Neuropathy ◽  
Withdrawal Threshold ◽  
Spinal Dorsal ◽  
Paclitaxel Treatment

Abstract Background The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat solid tumor, is painful neuropathy. However, the molecular mechanisms underlying paclitaxel-induced painful neuropathy are largely unclarified. Methods Paw withdrawal threshold was measured in the rats following intraperitoneal injection of paclitaxel. The qPCR, western blotting, protein or chromatin immunoprecipitation, ChIP-seq identification of NFATc2 binding sites, and microarray analysis were performed to explore the molecular mechanism. Results We found that paclitaxel treatment increased the nuclear expression of NFATc2 in the spinal dorsal horn, and knockdown of NFATc2 with NFATc2 siRNA significantly attenuated the mechanical allodynia induced by paclitaxel. Further binding site analysis utilizing ChIP-seq assay combining with gene expression profile revealed a shift of NFATc2 binding site closer to TTS of target genes in dorsal horn after paclitaxel treatment. We further found that NFATc2 occupancy may directly upregulate the chemokine CXCL14 expression in dorsal horn, which was mediated by enhanced interaction between NFATc2 and p300 and consequently increased acetylation of histone H4 in CXCL14 promoter region. Also, knockdown of CXCL14 in dorsal horn significantly attenuated mechanical allodynia induced by paclitaxel. Conclusion These results suggested that enhanced interaction between p300 and NFATc2 mediated the epigenetic upregulation of CXCL14 in the spinal dorsal horn, which contributed to the chemotherapeutic paclitaxel-induced chronic pain.

scholarly journals NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel

2020 ◽  
Author(s):  
Meng Liu ◽  
Su-Bo Zhang ◽  
Yu-Xuan Luo ◽  
Yan-Ling Yang ◽  
Xiang-Zhong Zhang ◽  
...  
Keyword(s):  
Binding Site ◽  
Dorsal Horn ◽  
Mechanical Allodynia ◽  
Spinal Dorsal Horn ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Painful Neuropathy ◽  
Withdrawal Threshold ◽  
Spinal Dorsal ◽  
Paclitaxel Treatment

Abstract Background: The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat solid tumor, is painful neuropathy. However, the molecular mechanisms underlying paclitaxel-induced painful neuropathy are largely unclarified. Methods: Paw withdrawal threshold was measured in the rats following intraperitoneal injection of paclitaxel. The qPCR, western blotting, protein or chromatin immunoprecipitation, ChIP-seq identification of NFATc2 binding sites, microarray analysis were performed to explore the molecular mechanism. Results: We found that paclitaxel treatment increased the expression of NFATc2 in the spinal dorsal horn, and knockdown of NFATc2 with NFATc2 siRNA significantly attenuated the mechanical allodynia induced by paclitaxel. Further binding site analysis utilizing ChIP-seq assay combining with gene expression profile revealed a shift of NFATc2 binding site closer to TSS of target genes in dorsal horn after paclitaxel treatment. We further found that NFATc2 occupancy directly upregulated the chemokine CXCL14 expression in dorsal horn, which was mediated by enhanced interaction between NFATc2 and p300 and consequently increased acetylation of histone H4 in CXCL14 promoter region. Also, knockdown of CXCL14 in dorsal horn significantly attenuated mechanical allodynia induced by paclitaxel. Conclusion: These results suggested that enhanced interaction between p300 and NFATc2 mediated the epigenetic upregulation of CXCL14 in the spinal dorsal horn, which contributed to the chemotherapeutic paclitaxel-induced chronic pain.

Liver X Receptor α Is Involved in Counteracting Mechanical Allodynia by Inhibiting Neuroinflammation in the Spinal Dorsal Horn

2017 ◽  
Vol 127 (3) ◽  
pp. 534-547 ◽  
Author(s):  
Jing Xu ◽  
Yi-Wei Feng ◽  
Ling Liu ◽  
Wei Wang ◽  
Xiong-Xiong Zhong ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Glial Cells ◽  
Mechanical Allodynia ◽  
Spinal Dorsal Horn ◽  
Liver X Receptor ◽  
Spared Nerve Injury ◽  
Wild Type ◽  
Spinal Dorsal ◽  
Liver X Receptor Α

Abstract Background Liver X receptors, including α and β isoforms, are ligand-activated transcription factors. Whether liver X receptor α plays a role in neuropathic pain is unknown. Methods A spared nerve injury model was established in adult male rats and mice. Von Frey tests were performed to evaluate the neuropathic pain behavior; Western blot and immunohistochemistry were performed to understand the underlying mechanisms. Results Intrathecal injection of a specific liver X receptor agonist T0901317 or GW3965 could either prevent the development of mechanical allodynia or alleviate the established mechanical allodynia, both in rats and wild-type mice. GW3965 could inhibit the activation of glial cells and the expression of tumor necrosis factor-α (mean ± SD: 196 ± 48 vs. 119 ± 57; n = 6; P < 0.01) and interleukin 1β (mean ± SD: 215 ± 69 vs. 158 ± 74; n = 6; P < 0.01) and increase the expression of interleukin 10 in the spinal dorsal horn. All of the above effects of GW3965 could be abolished by liver X receptor α mutation. Moreover, more glial cells were activated, and more interleukin 1β was released in the spinal dorsal horn in liver X receptor α knockout mice than in wild-type mice after spared nerve injury. Aminoglutethimide, a neurosteroid synthesis inhibitor, blocked the inhibitory effect of T0901317 on mechanical allodynia, on the activation of glial cells, and on the expression of cytokines. Conclusions Activation of liver X receptor α inhibits mechanical allodynia by inhibiting the activation of glial cells and rebalancing cytokines in the spinal dorsal horn via neurosteroids.

scholarly journals Resveratrol Mediates Mechanical Allodynia Through Modulating Inflammatory Response via the TREM2-autophagy Axis in SNI Rat Model

2020 ◽  
Author(s):  
Yaping Wang ◽  
Yu Shi ◽  
Yongquan Huang ◽  
Wei Liu ◽  
Guiyuan Cai ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Inflammatory Response ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Rat Model ◽  
Mechanical Allodynia ◽  
Spinal Dorsal Horn ◽  
Intrathecal Administration ◽  
Spared Nerve Injury ◽  
Spinal Dorsal

Abstract Background Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. Methods A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanism allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, Lentivirus coding TREM2 was intrathecal injected into SNI rats to activate TREM2 and the pain behavior was detected by the Von Frey test. Furthermore, 3-Methyladenine (3-MA, an autophagy inhibitor) was performed to analyze the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, immunofluorescence. Results The TREM2 expression and number of the microglial cell was significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-methyladenine in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. Conclusions Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.

scholarly journals Proteomics Analysis of the Spinal Dorsal Horn in Diabetic Painful Neuropathy Rats With Electroacupuncture Treatment

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiangmei Yu ◽  
Xiaomei Chen ◽  
Weiting Liu ◽  
Menghong Jiang ◽  
Zhifu Wang ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Fasting Blood Glucose ◽  
Male Rats ◽  
Tandem Mass ◽  
Painful Neuropathy ◽  
Proteomics Analysis ◽  
Spinal Dorsal ◽  
Diabetic Painful Neuropathy

BackgroundClinical evidence demonstrates that electro-acupuncture (EA) of the Zu sanli (ST36) and Shen shu (BL23) acupoints is effective in relieving diabetic painful neuropathy (DPN); however, the underlying molecular mechanism requires further investigation, including the protein molecules associated with EA’s effects on DPN.MethodsSprague-Dawley adult male rats (n =36) were randomly assigned into control, DPN, and EA groups (n=12 each). After four weeks of EA treatment, response to mechanical pain and fasting blood glucose were analyzed. A tandem mass tag (TMT) labeling approach coupled with liquid chromatography with tandem mass spectrometry was used to identify potential biomarkers in the spinal dorsal horn. Further, proteomics analysis was used to quantify differentially expressed proteins (DEPs), and gene ontology, KEGG pathways, cluster, and string protein network interaction analyses conducted to explore the main protein targets of EA.ResultsCompared with the DPN model group, the mechanical pain threshold was significantly increased, while the fasting blood glucose levels were clearly decreased in EA group rats. Proteomics analysis was used to quantify 5393 proteins, and DEPs were chosen for further analyses, based on a threshold of 1.2-fold difference in expression level (P < 0.05) compared with control groups. Relative to the control group, 169 down-regulated and 474 up-regulated proteins were identified in the DPN group, while 107 and 328 proteins were up- and down-regulated in the EA treatment group compared with the DPN group. Bioinformatics analysis suggested that levels of proteins involved in oxidative stress injury regulation were dramatically altered during the EA effects on DPN.ConclusionsOur results provide the valuable protein biomarkers, which facilitates unique mechanistic insights into the DPN pathogenesis and EA analgesic, antioxidant stress and hypoglycemic effect.

scholarly journals https://painphysicianjournal.com/current/pdf?article=MTgwMw%3D%3D&journal=71

2012 ◽  
Vol 6;15 (6;12) ◽  
pp. E995-E1006
Author(s):  
Prof. Yun-Qing Li
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Inflammatory Cytokines ◽  
Glial Cells ◽  
Mechanical Allodynia ◽  
Spinal Dorsal Horn ◽  
Pain Behavior ◽  
Repeated Treatment ◽  
Single Bolus ◽  
Spinal Dorsal

Background: Current treatments for neuropathic pain are far from satisfactory. Considering the essential contribution of central immune factors to the pathogenesis of neuropathic pain, targeting inflammatory response is well accepted as an effective strategy for treating neuropathic pain. Triptolide has a long history in traditional Chinese medicine for treating inflammatory diseases and has been proven to inhibit cytokines released from glial cells. Objective: In the present study, we tested whether systemic treatment with triptolide could prevent or attenuate nocifensive behaviors associated with neuropathic pain. We further tried to explore the underlying mechanism of the potential anti-allodynia effect of triptolide. Study Design: A randomized, double blind, controlled animal trial. Methods: Triptolide was administered systemically in a rat model of neuropathic pain induced by spinal nerve ligation (SNL) in the single bolus and repeated treatment manners. In the single bolus treatment experiment, triptolide (30 μg/kg, 100 μg/kg, 300 μg/kg) or vehicle was given to SNL and sham-operated rats once on day 1 or on day 10 after surgery (n = 6 each). In the repeated treatment study, prophylactic treatment with triptolide (30 μg/kg, 100 μg/kg, 300 μg/kg) was given to rats during the period of day -3 (3 days prior to SNL) to day 7 (7 days post-SNL) inclusively (n = 6 each). Another set of SNL and sham rats on postoperative day 10 received treatment with triptolide (30 μg/kg, 100 μg/kg, 300 μg/kg) or vehicle during the period of days 11–20 inclusively (n = 6 each), to assess potential reversal of established pain behavior. Mechanical allodynia of the rats was tested with von Frey filaments. Astrocytic and microglial activation in the spinal dorsal horn was evaluated with immunofluorescent histochemistry. Phosphorylation of mitogen-activated protein kinases (MAPKs), and expression of inflammatory cytokines (interleukin-6, interleukin-1beta, monocyte chemotactic protein-1, and tumor necrosis factor-alpha) were examined with Western blot analysis and real-time reverse transcription polymerase chain reaction study. Results: A single bolus treatment with triptolide could neither prevent the induction nor reverse the maintenance of SNL-induced mechanical allodynia. However, repeated administration of triptolide dose-dependently inhibited neuropathic pain behavior in both preventative and interventional paradigms. Triptolide hampered SNL-induced activation of glial cells (astrocytes and microglia) in the spinal dorsal horn without influencing neurons. In addition, SNL-induced phosphorylation of MAPKs could be inhibited by triptolide. Furthermore, up-regulated expression of inflammatory cytokines in neuropathic pain states could be remarkably blocked by triptolide. Limitations: The direct target site (such as a specific receptor) of triptolide is still to be determined. In addition, triptolide could not completely block the SNL-induced mechanical allodynia. Conclusions: Our data suggest that triptolide may be a potential novel treatment for neuropathic pain through modulating immune response in the spinal dorsal horn. Key words: Triptolide, neuropathic pain, spinal dorsal horn, astrocyte, microglia, MAPK.

Intrathecal Lidocaine Reverses Tactile Allodynia Caused by Nerve Injuries and Potentiates the Antiallodynic Effect of the COX Inhibitor Ketorolac

2003 ◽  
Vol 98 (1) ◽  
pp. 203-208 ◽  
Author(s):  
Weiya Ma ◽  
Wei Du ◽  
James C. Eisenach
Keyword(s):  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Spinal Nerve ◽  
Tactile Allodynia ◽  
Withdrawal Threshold ◽  
Dorsal Horn Neurons ◽  
Spinal Dorsal ◽  
Cox Inhibitor ◽  
Antiallodynic Effect ◽  
Von Frey Filaments

Background Systemic lidocaine and other local anesthetics reduce hypersensitivity states induced by both acute inflammation and peripheral nerve injury in animals and produce analgesia in some patients with chronic pain. The mechanisms underlying the antiallodynic effect of systemic lidocaine are unclear, although most focus is on peripheral mechanisms. Central mechanisms, particularly at the spinal dorsal horn level, are less known. In this study, the authors aimed to determine whether intrathecal lidocaine has an antiallodynic effect on established mechanical allodynia in two well-characterized neuropathic pain rat models: partial sciatic nerve ligation (PSNL) and spinal nerve ligation (SNL). Methods Lidocaine (100-300 micro g) was intrathecally injected in PSNL and SNL rats. The withdrawal threshold of both hind paws in response to mechanical stimulation was measured using a series of calibrated von Frey filaments. Results This single injection reduced ongoing tactile allodynia in PSNL and SNL rats. The antiallodynic effect of intrathecal lidocaine lasted longer in PSNL (> 3 days) than in SNL rats (< 3 days). Intraperitoneal lidocaine (300 micro g) had no effect on tactile allodynia in PSNL rats. In SNL rats, prior intrathecal lidocaine (200 and 300 micro g) potentiated the antiallodynic effect of intrathecal ketorolac, a nonselective cyclooxygenase inhibitor. Intrathecal ketorolac alone had no antiallodynic effect on SNL rats. However, prior intrathecal lidocaine (100 micro g) failed to potentiate the antiallodynic effect of intrathecal ketorolac. Conclusion The authors' data suggest that intrathecal lidocaine possibly suppressed the hyperexcitability of the dorsal horn neurons and likely interacted with eicosanoid systems in the spinal dorsal horn.

scholarly journals The Inhibitory Effect of Somatostatin Receptor Activation on Bee Venom-Evoked Nociceptive Behavior and pCREB Expression in Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Li Li ◽  
Rong Luo ◽  
Yuan Guo ◽  
Fanrong Yao ◽  
Dongyuan Cao ◽  
...  
Keyword(s):  
Dorsal Horn ◽  
Mechanical Allodynia ◽  
Spinal Dorsal Horn ◽  
Somatostatin Receptor ◽  
Thermal Hyperalgesia ◽  
Receptor Activation ◽  
Bee Venom ◽  
Spinal Dorsal ◽  
Nociceptive Responses ◽  
Lumbar Spinal

The present study examined nociceptive behaviors and the expression of phosphorylated cAMP response element-binding protein (pCREB) in the dorsal horn of the lumbar spinal cord and the dorsal root ganglion (DRG) evoked by bee venom (BV). The effect of intraplantar preapplication of the somatostatin analog octreotide on nociceptive behaviors and pCREB expression was also examined. Subcutaneous injection of BV into the rat unilateral hindpaw pad induced significant spontaneous nociceptive behaviors, primary mechanical allodynia, primary thermal hyperalgesia, and mirror-thermal hyperalgesia, as well as an increase in pCREB expression in the lumbar spinal dorsal horn and DRG. Octreotide pretreatment significantly attenuated the BV-induced lifting/licking response and mechanical allodynia. Local injection of octreotide also significantly reduced pCREB expression in the lumbar spinal dorsal horn and DRG. Furthermore, pretreatment with cyclosomatostatin, a somatostatin receptor antagonist, reversed the octreotide-induced inhibition of the lifting/licking response, mechanical allodynia, and the expression of pCREB. These results suggest that BV can induce nociceptive responses and somatostatin receptors are involved in mediating the antinociception, which provides new evidence for peripheral analgesic action of somatostatin in an inflammatory pain state.

Sign in / Sign up

Export Citation Format

Share Document