Single Intraperitoneal Injection of Low-Dose Ketamine Pretreatment Alleviates Mechanical Hyperalgesia and Downregulates the Expression of Inflammatory Cytokines in Spinal Dorsal Horn of Rats

2015 ◽  
Vol 2 (5) ◽  
pp. 236-243
Author(s):  
Li Xu ◽  
Yu Shen ◽  
Lin Liu ◽  
Yin Cui ◽  
Xiao-Ping Gu ◽  
...  
Keyword(s):  
Dorsal Horn ◽  
Inflammatory Cytokines ◽  
Intraperitoneal Injection ◽  
Spinal Dorsal Horn ◽  
Low Dose ◽  
Mechanical Hyperalgesia ◽  
Spinal Dorsal ◽  
Single Intraperitoneal Injection

scholarly journals Prophylactic Repetitive Treatment with the Herbal Medicine Kei-kyoh-zoh-soh-oh-shin-bu-toh Attenuates Oxaliplatin-Induced Mechanical Allodynia by Decreasing Spinal Astrocytes

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Tsugunobu Andoh ◽  
Daisuke Fukutomi ◽  
Daisuke Uta ◽  
Yasushi Kuraishi
Keyword(s):  
Dorsal Horn ◽  
Intraperitoneal Injection ◽  
Mechanical Allodynia ◽  
Spinal Dorsal Horn ◽  
Chemotherapeutic Drugs ◽  
Neuregulin 1 ◽  
Spinal Dorsal ◽  
Herbal Formulation ◽  
Single Intraperitoneal Injection ◽  
Single Oral Administration

Chemotherapeutic drugs typically induce peripheral neuropathy, which is a major dose-limiting side effect of these drugs and is difficult to manage. In this study, we examined whether the traditional herbal formulation Kei-kyoh-zoh-soh-oh-shin-bu-toh (KSOT) could relieve the mechanical allodynia induced by chemotherapeutic drugs (oxaliplatin, paclitaxel, vincristine, and bortezomib) in mice. A single intraperitoneal injection of oxaliplatin, paclitaxel, vincristine, and bortezomib was used to induce mechanical allodynia, which peaked on days 10, 14, 14, and 12 after the injection, respectively. A single oral administration of KSOT did not inhibit mechanical allodynia after any of the treatments. However, prophylactic repetitive oral administrations of KSOT inhibited the exacerbation of mechanical allodynia induced by oxaliplatin but were not effective for allodynia induced by the other drugs. A single intraperitoneal injection of oxaliplatin did not alter the mRNA expression of the NMDA receptor NR2B in the spinal cord and that of neuregulin-1 in the sciatic nerve. In addition, the number of microglia in spinal dorsal horn did not increase in oxaliplatin-treated mice. However, the number of reactivated astrocytes in the spinal dorsal horn increased, which could be inhibited by repetitive administration of KSOT. These results suggest that prophylactic repetitive treatment of KSOT attenuates oxaliplatin-induced mechanical allodynia by decreasing the number of spinal astrocytes.

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.

scholarly journals Mechanism of Incisional Pain: Novel Finding on Long Noncoding RNA XIST/miR-340-5p/RAB1A Axis

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110490
Author(s):  
Juan Liao ◽  
Fan Zhang ◽  
Wenxiang Qing ◽  
Rili Yu ◽  
Zhonghua Hu*
Keyword(s):  
Postoperative Pain ◽  
Dorsal Horn ◽  
Inflammatory Cytokines ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Spinal Dorsal Horn ◽  
Tunel Staining ◽  
Spinal Dorsal ◽  
Lncrna Xist ◽  
Plantar Incision

The objective of this study is to investigate the effect of long noncoding RNA (lncRNA) XIST on postoperative pain and inflammation of plantar incision pain (PIP) in rats and its underlying mechanisms. PIP rat models were established by plantar incision. Rats in the sham group were subjected to povidone-iodine scrubbing, and no incision was made. To explore the role of XIST/ miR-340-5p/RAB1A in postoperative pain and inflammation, PIP rats were separately or simultaneously injected with lentivirus containing sh-NC, sh-XIST, mimic NC, miR-340-5p mimic, inhibitor NC, miR-340-5p inhibitor, pcDNA3.1, or pcDNA3.1-RAB1A through an intrathecal catheter. The paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) values of rats in each group were assessed to evaluate the pain behavior. RT-qPCR and Western blot were utilized to determine the levels of XIST, miR-340-5p, RAB1A, and NF-κB pathway-related proteins (p-IκBα, IκBα, p-p65, and p65). The concentrations of inflammatory cytokines (TNF-α, IL-1β, and IL-6) in rat spinal dorsal horn tissues were inspected by ELISA. H and E staining was applied to observe the pathological changes of neurons in the spinal dorsal horn, TUNEL staining to detect neuronal apoptosis, and immunohistochemistry to measure RAB1A level. Plantar incision surgery caused decreased PWT and PWL values, enhanced levels of XIST, RAB1A, and inflammatory cytokines, along with an increased proportion of apoptotic neurons. The pain sensitivity and inflammation of rats were motivated after plantar incision surgery. Intrathecal injection of sh-XIST or miR-340-5p mimic ameliorated the pain and inflammation of PIP rats, while silencing of miR-340-5p or overexpression of RAB1A partly reversed the effect of sh-XIST on PIP rats. XIST targeted miR-340-5p and miR-340-5p negatively regulated RAB1A. The XIST/ miR-340-5p/RAB1A axis activated the NF-κB signaling pathway. LncRNA XIST aggravates inflammatory response and postoperative pain of PIP rats by activating the NF-κB pathway via the miR-340-5p/RAB1A axis.

Role of Prostaglandin Receptor EP1in the Spinal Dorsal Horn in Carrageenan-induced Inflammatory Pain

2002 ◽  
Vol 97 (5) ◽  
pp. 1254-1262 ◽  
Author(s):  
Yoshito Nakayama ◽  
Keiichi Omote ◽  
Akiyoshi Namiki
Keyword(s):  
Dorsal Horn ◽  
Inflammatory Pain ◽  
Early Phase ◽  
Spinal Dorsal Horn ◽  
Late Phase ◽  
Mechanical Hyperalgesia ◽  
Ion Concentration ◽  
Ipsilateral Side ◽  
Spinal Dorsal ◽  
Pge2 Concentration

Background Prostaglandin E2 (PGE2) and the receptor for PGE2 (EP receptor) are key factors contributing to the generation of hyperalgesia caused by inflammation. The current study was designed to investigate the roles of PGE2 and EP1 receptors in the spinal cord in the development and maintenance of inflammatory pain, using behavioral, microdialysis, and intracellular calcium ion concentration ([Ca2+]i) assays. Methods Inflammation was induced by an injection of carrageenan into the plantar surface of the rat hind paw. The effects of inflammation were evaluated at the time points of 3 h (early phase) and 15 h (late phase) after carrageenan injection. In behavioral assays, withdrawal thresholds to mechanical stimuli were evaluated. The effect of an intrathecally administered selective EP1 antagonist, ONO-8711, on the carrageenan-induced hyperalgesia was examined. Using a spinal microdialysis method, PGE2 concentration in the spinal dorsal horn was measured. In [Ca2+]i assays, we measured [Ca2+]i in the spinal dorsal horn in transverse spinal slices and examined the effects of pretreatment with ONO-8711. Sensitivities of the changes in [Ca2+]i to PGE2 perfusion were also assessed. Results Mechanical hyperalgesia and paw edema were observed in both the early and late phases. The hyperalgesia was inhibited by intrathecal ONO-8711 in the late, but not early, phase. The concentration of PGE2 in the spinal dorsal horn increased in the late phase. The [Ca2+]i in the dorsal horn increased on the ipsilateral side to the inflammation in the late, but not early phase. This increase was suppressed by the pretreatment with ONO-8711. Magnitude of the increase in [Ca2+]i on the ipsilateral side in response to PGE2 perfusion was greater in the late phase than in the early phase. Conclusion The results suggested that activation of spinal EP1 receptors was crucial in the carrageenan-induced mechanical hyperalgesia in the late phase. It seems that some of the mechanisms underlying inflammation-induced plastic changes are mediated by time-dependent increase in PGE2 concentration, activation of EP1 receptors, and increase in [Ca2+]i in the spinal dorsal horn.

scholarly journals Calcitonin gene-related peptide regulates spinal microglial activation through the histone H3 lysine 27 trimethylation via enhancer of zeste homolog-2 in rats with neuropathic pain

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Qi An ◽  
Chenyan Sun ◽  
Ruidi Li ◽  
Shuhui Chen ◽  
Xinpei Gu ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Spinal Dorsal Horn ◽  
Microglial Activation ◽  
Microglial Cells ◽  
Gene Promoters ◽  
Spinal Dorsal ◽  
Related Peptide ◽  
Calcitonin Gene

Abstract Background Calcitonin gene-related peptide (CGRP) as a mediator of microglial activation at the transcriptional level may facilitate nociceptive signaling. Trimethylation of H3 lysine 27 (H3K27me3) by enhancer of zeste homolog 2 (EZH2) is an epigenetic mark that regulates inflammatory-related gene expression after peripheral nerve injury. In this study, we explored the relationship between CGRP and H3K27me3 in microglial activation after nerve injury, and elucidated the underlying mechanisms in the pathogenesis of chronic neuropathic pain. Methods Microglial cells (BV2) were treated with CGRP and differentially enrichments of H3K27me3 on gene promoters were examined using ChIP-seq. A chronic constriction injury (CCI) rat model was used to evaluate the role of CGRP on microglial activation and EZH2/H3K27me3 signaling in CCI-induced neuropathic pain. Results Overexpressions of EZH2 and H3K27me3 were confirmed in spinal microglia of CCI rats by immunofluorescence. CGRP treatment induced the increased of H3K27me3 expression in the spinal dorsal horn and cultured microglial cells (BV2) through EZH2. ChIP-seq data indicated that CGRP significantly altered H3K27me3 enrichments on gene promoters in microglia following CGRP treatment, including 173 gaining H3K27me3 and 75 losing this mark, which mostly enriched in regulation of cell growth, phagosome, and inflammation. qRT-PCR verified expressions of representative candidate genes (TRAF3IP2, BCL2L11, ITGAM, DAB2, NLRP12, WNT3, ADAM10) and real-time cell analysis (RTCA) verified microglial proliferation. Additionally, CGRP treatment and CCI increased expressions of ITGAM, ADAM10, MCP-1, and CX3CR1, key mediators of microglial activation in spinal dorsal horn and cultured microglial cells. Such increased effects induced by CCI were suppressed by CGRP antagonist and EZH2 inhibitor, which were concurrently associated with the attenuated mechanical and thermal hyperalgesia in CCI rats. Conclusion Our findings highly indicate that CGRP is implicated in the genesis of neuropathic pain through regulating microglial activation via EZH2-mediated H3K27me3 in the spinal dorsal horn.

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