Attenuation of Remifentanil-Induced Hyperalgesia by Betulinic Acid Associates with Inhibiting Oxidative Stress and Inflammation in Spinal Dorsal Horn

Pharmacology ◽  
2018 ◽  
Vol 102 (5-6) ◽  
pp. 300-306 ◽  
Author(s):  
Chang-Cheng Lv ◽  
Man-Li Xia ◽  
Shu-Juan Shu ◽  
Fei Chen ◽  
Li-Shan Jiang
Keyword(s):  
Oxidative Stress ◽  
Dorsal Horn ◽  
Betulinic Acid ◽  
Spinal Dorsal Horn ◽  
Manganese Superoxide Dismutase ◽  
Visceral Pain ◽  
Sprague Dawley ◽  
Spinal Dorsal ◽  
Pre Treatment ◽  
Factor Α

Remifentanil-induced hyperalgesia (RIH) is known to be associated with oxidative stress and inflammation. Betulinic acid (BA) was reported to reduce visceral pain owing to its anti-oxidative and anti-inflammatory potential. Here, we ­explored whether BA can attenuate RIH through inhibiting oxidative stress and inflammation in spinal dorsal horn. Sprague-Dawley rats were randomly divided into 4 groups: Control, Incision, RIH, and RIH pre-treated with BA. After pretreated with BA (25 mg/kg, i.g.) for 7 days, rats were subcutaneously infused with remifentanil (40 μg/kg) for 30 min during right plantar incision surgery to induce RIH. The paw withdrawal mechanical threshold (PWMT), paw withdrawal thermal latency (PWTL), spinal oxidative stress and inflammatory mediators were determined. Intraoperative remifentanil infusion induced postoperative hyperalgesia, as evidenced by the significant decrease in PWMT and PWTL (p < 0.01), and the significant increase in oxidative stress and inflammation evidenced by up-regulations of malondialdehyde, 3-nitrotyrosine, interleukin-1β and tumour necrosis factor-α (p < 0.01) in spinal dorsal horn and matrix metalloproteinase-9 (MMP-9) activity (p < 0.01) in dorsal root ganglion, as well as a decrease in manganese superoxide ­dismutase activity (p < 0.01) compared with control and ­incision groups. All these results mentioned above were markedly reversed by pre-treatment with BA (p < 0.01) compared with RIH group. These findings demonstrated that BA can effectively attenuate RIH, which associates with potentially inhibiting oxidative stress and subsequently down-regulating MMP-9-related pro-inflammatory cyokines in spinal dorsal horn.

scholarly journals Antigen retrieval pre-treatment causes a different expression pattern of Cav3.2 in rat and mouse spinal dorsal horn

2019 ◽  
Vol 63 (1) ◽  
Author(s):  
Xiao E Cheng ◽  
Long Xian Ma ◽  
Xiao Jin Feng ◽  
Meng Ye Zhu ◽  
Da Ying Zhang ◽  
...  
Keyword(s):  
Dorsal Horn ◽  
Expression Pattern ◽  
Spinal Dorsal Horn ◽  
Antigen Retrieval ◽  
Neuronal Marker ◽  
Nociceptive Neurons ◽  
Spinal Dorsal ◽  
Pathological Pain ◽  
Pre Treatment ◽  
Rats And Mice

Cav3 channels consist of three isoforms, Cav3.1 (α1G), Cav3.2 (α1H), and Cav3.3 (α1I), which produce low-threshold spikes that trigger burst firings in nociceptive neurons of the spinal dorsal horn (SDH) and dorsal root ganglion (DRG). Although Cav3.2 plays a crucial role in pathological pain, its distribution in SDH still remains controversial. One study showed that Cav3.2 is ubiquitously expressed in neurons, but another study implied that Cav3.2 is expressed restricted to astrocytes. To unravel these discrepancies, we used methods of immunohistochemistry either with or without antigen retrieval (AR) pre-treatment to detect Cav3 in SDH and DRG from both rats and mice. Moreover, Cav3.2 mRNA was detected in mice SDH using in situ hybridization. We found that the expression pattern of Cav3.2 but not Cav3.1 and Cav3.3 in SDH were largely different with or without AR pre-treatment, which showed a neuron-like and an astrocyte-like appearance, respectively. Double staining further demonstrated that Cav3.2 was mainly co-stained with the neuronal marker NeuN in the presence of AR but was with glial fibrillary acidic protein (GFAP, marker for astrocytes) in the absence of AR pre-treatment. Importantly, Cav3.2 mRNA was mainly co-localized with Cav3.2 but not GFAP. Together, our findings indicate that AR pre-treatment or not impacts the expression pattern of Cav3.2, which may make a significant contribution to the future study of Cav3.2 in SDH.

scholarly journals Involvement of Brn3a-positive spinal dorsal horn neurons in the transmission of visceral pain in inflammatory bowel disease model mice

2021 ◽  
Author(s):  
Kazuhiko Nishida ◽  
Shinji Matsumura ◽  
Takuya Kobayashi
Keyword(s):  
Inflammatory Bowel Disease ◽  
Dorsal Horn ◽  
Bowel Disease ◽  
Spinal Dorsal Horn ◽  
Visceral Pain ◽  
Dorsal Horn Neurons ◽  
Spinal Dorsal ◽  
Pain Transmission ◽  
Inflammatory Bowel ◽  
Spinal Dorsal Horn Neurons

Spinal dorsal horn plays crucial roles in the transmission and processing of somatosensory information. Although spinal neural circuits which process several distinct types of cutaneous sensation have been extensively studied, those responsible for visceral pain transmission remain poorly understood. In the present study, we analyzed the dextran sodium sulfate (DSS)-induced inflammatory bowel disease (IBD) model mice to characterize the spinal dorsal horn neurons involved in visceral pain transmission. DSS-treated mice exhibited increased abdominal licking behavior, suggestive of experiencing visceral pain. Immunostaining of c-fos, a marker indicating neuronal activity, demonstrated that numerous c-fos-positive cells were found bilaterally in the lumbosacral spinal dorsal horn, and their distribution was particularly abundant in the shallow dorsal horn. Neurochemical characterization of these neurons revealed that the percentage of the POU transcription factor Brn3a-positive neurons among the c-fos-positive neurons in the shallow dorsal horn was 30-40% in DSS-treated mice, which was significantly higher than that in the somatic pain model mice. We further demonstrated by neuronal tracing that within the shallow dorsal horn, Brn3a-positive neurons are represented more highly in spino-solitary projection neurons than in spino-parabrachial projection ones. These results raised the possibility that Brn3a-positive spinal dorsal horn neurons make a large contribution to visceral pain transmission, and part of which was mediated through spino-solitary pathway.

scholarly journals Upregulation of Spinal ASIC1 and NKCC1 Expression Contributes to Chronic Visceral Pain in Rats

2021 ◽  
Vol 13 ◽  
Author(s):  
Yong-Chang Li ◽  
Yuan-Qing Tian ◽  
Yan-Yan Wu ◽  
Yu-Cheng Xu ◽  
Ping-An Zhang ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Signaling Pathway ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Visceral Pain ◽  
Intrathecal Injection ◽  
Adult Rats ◽  
Sodium Potassium ◽  
Spinal Dorsal ◽  
Whole Cell Patch Clamp

Aims: To determine whether acid-sensing ion channel 1 (ASIC1)–sodium-potassium-chloride cotransporter 1 (NKCC1) signaling pathway participates in chronic visceral pain of adult rats with neonatal maternal deprivation (NMD).Methods: Chronic visceral pain was detected by colorectal distension (CRD). Western blotting and Immunofluorescence were performed to detect the expression and location of ASIC1 and NKCC1. Whole-cell patch-clamp recordings were performed to record spinal synaptic transmission.Results: The excitatory synaptic transmission was enhanced and the inhibitory synaptic transmission was weakened in the spinal dorsal horn of NMD rats. ASIC1 and NKCC1 protein expression in the spinal dorsal horn was significantly up-regulated in NMD rats. Incubation of Amiloride reduced the amplitude of mEPSCs. Incubation of Bumetanide (BMT) increased the amplitude of mIPSCs. Intrathecal injection of ASIC1 or NKCC1 inhibitors reversed the threshold of CRD in NMD rats. Also, Amiloride treatment significantly reversed the expression of NKCC1 in the spinal dorsal horn of NMD rats.Conclusion: Our data suggest that the ASIC1-NKCC1 signaling pathway is involved in chronic visceral pain in NMD rats.

scholarly journals Targeting spinal TRAF6 expression attenuates chronic visceral pain in adult rats with neonatal colonic inflammation

2020 ◽  
Vol 16 ◽  
pp. 174480692091805 ◽  
Author(s):  
Rui-Xia Weng ◽  
Wei Chen ◽  
Jia-Ni Tang ◽  
Qian Sun ◽  
Meng Li ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Irritable Bowel Syndrome ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Visceral Pain ◽  
Intrathecal Injection ◽  
Visceral Hypersensitivity ◽  
Colonic Inflammation ◽  
Spinal Dorsal ◽  
Irritable Bowel

Background Irritable bowel syndrome is one of the most common gastrointestinal disorders. It is featured by abdominal pain in conjunction with altered bowel habits. However, the pathophysiology of the syndrome remains largely unknown. Tumor necrosis factor receptor-associated factor 6 (TRAF6) has been reported to be involved in neuropathic pain. The aim of this study was to investigate roles and mechanisms of TRAF6 in the chronic visceral hypersensitivity. Methods Visceral hypersensitivity was induced by neonatal colonic inflammation and was identified by colorectal distention. The protein level, RNA level, and cellular distribution of TRAF6 and its related molecules were detected with Western blot, quantitative polymerase chain reaction, and immunofluorescence. In vitro spinal cord slice recording technique was performed to determine the synaptic transmission activities. Results Neonatal colonic inflammation rats displayed visceral hypersensitivity at the age of six weeks. The expression of TRAF6 was obviously upregulated in spinal cord dorsal horn of neonatal colonic inflammation rats at the age of six weeks. Immunofluorescence study showed that TRAF6 was dominantly expressed in spinal astrocytes. Intrathecal injection of TRAF6 small interfering RNA (siRNA) significantly reduced the amplitude of spontaneous excitatory postsynaptic currents at the spinal dorsal horn level. Furthermore, knockdown of TRAF6 led to a significant downregulation of cystathionine β synthetase expression in the spinal dorsal horn of neonatal colonic inflammation rats. Importantly, intrathecal injection of TRAF6 siRNA remarkably alleviated visceral hypersensitivity of neonatal colonic inflammation rats. Conclusions Our results suggested that the upregulation of TRAF6 contributed to visceral pain hypersensitivity, which is likely mediated by regulating cystathionine β synthetase expression in the spinal dorsal horn. Our findings suggest that TRAF6 might act as a potential target for the treatment of chronic visceral pain in irritable bowel syndrome patients.

Effects of Halothane and Isoflurane on Hyperexcitability of Spinal Dorsal Horn Neurons after Incision in the Rat

2005 ◽  
Vol 102 (1) ◽  
pp. 165-174 ◽  
Author(s):  
Mikito Kawamata ◽  
Eichi Narimatsu ◽  
Yuji Kozuka ◽  
Toshiyuki Takahashi ◽  
Shigekazu Sugino ◽  
...  
Keyword(s):  
Spontaneous Activity ◽  
Dorsal Horn ◽  
Neuronal Activity ◽  
Spinal Dorsal Horn ◽  
Dynamic Range ◽  
Field Size ◽  
Control Group ◽  
Sprague Dawley ◽  
Dorsal Horn Neurons ◽  
Spinal Dorsal

Background The aim of this study was to determine whether halothane and isoflurane used during and after surgical injury attenuate subsequent hyperexcitability of spinal dorsal horn (SDH) neurons by preventing development of central sensitization. Methods Activity of a wide-dynamic-range neuron of the SDH was isolated in decerebrate-spinal Sprague-Dawley rats, and neuronal activity (receptive field size and responses to nonnoxious and noxious stimuli) was recorded. A 1-cm-long incision was made through the skin, fascia, and muscle under anesthesia with halothane (1.1% or 2.2%) and isoflurane (1.4% or 2.8%). Anesthesia was discontinued just after the incision had been made or was continued until 30 min after the incision, and activity of the SDH neurons was measured for up to 2 h after the incision. In a control group, the incision was made without anesthesia. Results In the control group, the incision resulted in maximum excitation in the SDH neurons during surgery; spontaneous activity significantly increased for up to 30 min after the incision (P &lt; 0.05) but did not significantly increase thereafter, returning to the preincision value. Halothane and isoflurane suppressed excitation of the neurons during the incision in a concentration-related manner. Administration of 2.2% halothane and 2.8% isoflurane during the incision and for up to 30 min after the incision almost abolished activity of the neurons for 30 min after the incision. The magnitude of neuronal activity 2 h after the incision was not significantly different among all groups, including the control group. Conclusions The results demonstrate that administration of halothane and isoflurane does not attenuate development of hyperexcitability of SDH neurons despite the fact that excitation and spontaneous activity during and after the incision were greatly suppressed by administration of halothane and isoflurane.

SIRT3 alleviates neuropathic pain by deacetylating FoxO3a in the spinal dorsal horn of diabetic model rats

2020 ◽  
Vol 46 (1) ◽  
pp. 49-56
Author(s):  
Chenghua Zhou ◽  
Yufeng Zhang ◽  
Xiaowei Jiao ◽  
Guizhi Wang ◽  
Ruiyao Wang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Western Blot ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Manganese Superoxide Dismutase ◽  
Antioxidant Genes ◽  
Pain Hypersensitivity ◽  
Spinal Dorsal ◽  
Manganese Superoxide ◽  
Underlying Mechanisms

BackgroundThe underlying mechanisms of neuropathic pain remain unclear. This work aimed to investigate the role of Sirtuin3 (SIRT3), an nicotinamide adenosine dinucleotide+-dependent histone deacetylase, in the development of neuropathic pain induced by type 2 diabetes mellitus (T2DM) and to explore the associated mechanisms.MethodsDiabetic neuropathic pain (DNP) in rats was induced by high-fat diet/low-dose streptozotocin. The pain behaviors were examined using the von Frey and Hargreaves tests. The levels of SIRT3, manganese superoxide dismutase (MnSOD) and catalase (CAT) were determined using Western blot and RT-qPCR. The acetylation, phosphorylation and ubiquitination of forkhead box class O3a (FoxO3a) were analyzed by immunoprecipitation and Western blot.ResultsSIRT3 expression and activity were significantly reduced in the spinal dorsal horn of DNP model rats. Overexpression of spinal SIRT3 reversed the pain hypersensitivity in the DNP model rats, but knockdown of spinal SIRT3 mimicked the pain effect, eliciting pain hypersensitivity in normal rats. Moreover, overexpression of spinal SIRT3 in DNP model rats increased the FoxO3a level and upregulated the antioxidant genes MnSOD and CAT by deacetylating FoxO3a and inhibiting FoxO3a phosphorylation and ubiquitination. Knockdown of spinal SIRT3 in normal rats decreased the FoxO3a level and downregulated MnSOD and CAT by inhibiting the deacetylation of FoxO3a and further increasing FoxO3a phosphorylation and ubiquitination.ConclusionsThese results suggest that, by deacetylating FoxO3a and further reducing its phosphorylation, ubiquitination and degradation in the spinal dorsal horn, SIRT3 stabilizes FoxO3a protein and inhibits oxidative stress, resulting in pain alleviation in T2DM model rats.

Electroacupuncture alleviates the transition from acute to chronic pain through the p38 MAPK/TNF-α signalling pathway in the spinal dorsal horn

2021 ◽  
pp. 096452842110207
Author(s):  
Ying Jin ◽  
Jie Zhou ◽  
Fangfang Xu ◽  
Zeqin Ren ◽  
Jun Hu ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Dorsal Horn ◽  
P38 Mapk ◽  
Spinal Dorsal Horn ◽  
Mitogen Activated Protein Kinase ◽  
Sprague Dawley ◽  
Necrosis Factor Alpha ◽  
Spinal Dorsal ◽  
Sd Rats ◽  
Tnf Α

Background: Hyperalgesic priming (HP) is a model of the transition from acute to chronic pain. Electroacupuncture (EA) could inhibit pain development through the peripheral dorsal root ganglia; however, it is unclear whether it can mitigate the transition from acute to chronic pain by attenuating protein expression in the p38 MAPK (mitogen-activated protein kinase)/tumour necrosis factor alpha (TNF-α) pathway in the spinal dorsal horn. Aims: We aimed to determine whether EA could prevent the transition from acute to chronic pain by affecting the p38 MAPK/TNF-α pathway in the spinal dorsal horn in a rat model established using HP. Methods: We first randomly subdivided 30 male Sprague-Dawley (SD) rats into 5 groups ( n = 6 per group): control (N), sham HP (Sham-HP), HP, HP + SB203580p38 MAPK (HP+SB203580), and HP + Lenalidomide (CC-5013) (HP+Lenalidomide). We then randomly subdivided a further 30 male SD rats into 5 groups ( n = 6 per group): Sham-HP, HP, sham EA (Sham EA), EA (EA), and EA + U-46619 p38 MAPK agonist (EA+U-46619). We assessed the effects of EA on the mechanical paw withdrawal threshold and p38 MAPK/TNF-α expression in the spinal dorsal horn of rats subjected to chronic inflammatory pain. Results: Rats in the EA group had reduced p38 MAPK and TNF-α expression and had significantly reduced mechanical hyperalgesia compared with rats in the other groups. Conclusion: Our findings indicate that EA could increase the mechanical pain threshold in rats and inhibit the transition from acute pain to chronic pain. This mechanism could involve reduced p38 MAPK/TNF-α expression in the spinal dorsal horn.

scholarly journals Effect of Electroacupuncture at ST36 on Gastric-Related Neurons in Spinal Dorsal Horn and Nucleus Tractus Solitarius

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Xiaoyu Wang ◽  
Hong Shi ◽  
Hongyan Shang ◽  
Wei He ◽  
Shuli Chen ◽  
...  
Keyword(s):  
Firing Rate ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Nucleus Tractus Solitarius ◽  
Sprague Dawley ◽  
Gastric Distention ◽  
Firing Rates ◽  
Spinal Dorsal ◽  
Sprague Dawley Rats ◽  
Significant Difference

The aim of this study was to observe the effect of electroacupuncture (EA) at the ST36 acupoint on the firing rate of gastric-related neurons in the spinal dorsal horn (SDH) and nucleus tractus solitarius (NTS). There were different effects of gastric distention in SDH and NTS in 46 male Sprague-Dawley rats. In 10 excitatory neurons in SDH, most of the neurons were inhibited by homolateral EA. The firing rates decreased significantly (P<0.05) in 10 excitatory gastric-related neurons in NTS; the firing rates of 6 neurons were further excited by homolateral EA, with a significant increase of the firing rates (P<0.05); all inhibitory gastric-related neurons in NTS were excited by EA. The inhibition rate of homolateral EA was significantly increased in comparison with contralateral EA in gastric-related neurons of SDH (P<0.05). There was no significant difference between homolateral and contralateral EA in gastric-related neurons of NTS. EA at ST36 changes the firing rate of gastric-related neurons in SDH and NTS. However, there are some differences in responsive mode in these neurons. The existence of these differences could be one of the physiological foundations of diversity and complexity in EA effects.

scholarly journals Effects of ghrelin on pGSK-3β and β-catenin expression when protects against neuropathic pain behavior in rats challenged with chronic constriction injury

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Zhiyou Peng ◽  
Leiqiong Zha ◽  
Meijuan Yang ◽  
Yunze Li ◽  
Xuejiao Guo ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Tumor Necrosis ◽  
Chronic Constriction Injury ◽  
Immunohistochemical Analysis ◽  
Spinal Dorsal ◽  
Gsk 3Β ◽  
Factor Α ◽  
Necrosis Factor

Abstract Ghrelin has been shown to alleviate neuropathic pain by inhibiting the release of proinflammatory cytokines. The purpose of this study was to investigate the role of GSK-3β/β-catenin signaling in mediating the effect of ghrelin on neuropathic pain and to understand the associated mechanisms. Chronic constriction injury (CCI) of the sciatic nerve was used to establish a rat model of neuropathic pain. Hyperalgesia and allodynia were evaluated by observing the mechanical withdrawal threshold and the thermal withdrawal latency. Wnt3a and β-catenin protein expression and GSK-3β phosphorylation were detected by western blotting analysis. The levels of tumor necrosis factor-α and IL-1β were determined using an enzyme-linked immunosorbent assay. In addition, we used immunohistochemical analysis to determine the levels of GSK-3β phosphorylation in the dorsal horn of the spinal cord. Intrathecal delivery of ghrelin effectively ameliorated CCI-induced mechanical allodynia and thermal hyperalgesia at 7 and 14 days and reduced the levels of tumor necrosis factor-α. Ghrelin inhibited CCI-induced GSK-3β activation and β-catenin overexpression in the spinal dorsal horn. Moreover, intrathecal injection of ghrelin suppressed the activation of GSK-3β in the spinal dorsal horn of CCI rats, as assessed by immunohistochemical analysis. Our data indicated that ghrelin could markedly alleviate neuropathic pain by inhibiting the expression of β-catenin, via the suppression of GSK-3β activation, in the spinal cord of CCI rats.

scholarly journals Blockade of Erythropoietin-Producing Human Hepatocellular Carcinoma Receptor B1 in Spinal Dorsal Horn Alleviates Visceral Pain in Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Chen-Li Sun ◽  
Cheng-Wen Li ◽  
Nong He ◽  
Yuan-Zhang Tang ◽  
Xiu-Liang Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Visceral Pain ◽  
Intrathecal Administration ◽  
Human Hepatocellular Carcinoma ◽  
Control Group ◽  
Visceral Hyperalgesia ◽  
Spinal Dorsal ◽  
Phosphorylated Form

Objective. This experiment was designed to determine whether erythropoietin-producing human hepatocellular carcinoma (Eph) receptors were involved in the development of visceral pain. Methods. Adult male Sprague-Dawley rats were randomly divided into three groups receiving different treatments (n = 16 per group): intracolonic vehicle (control group), intracolonic 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) (TNBS group), and intracolonic TNBS and intrathecal EphB1 receptor blocking reagent (TNBS + EphB2-Fc group). Visceral hyperalgesia was evaluated with quantification of visceral pain threshold induced by colorectal distention. The spinal expressions of EphB1 and ephrinB2 and levels of their phosphorylated forms (p-EphB1 and p-ephrinB2) were assessed by Western blotting and immunohistochemistry. Results. The TNBS-treated rats developed significant visceral hyperalgesia. The spinal expressions of EphB1, p-EphB1, ephrinB2, and p-ephrinB2 were significantly increased in the TNBS group compared with the control group, but visceral hyperalgesia and elevation of spinal EphB1 and p-EphB1 expressions were evidently alleviated by intrathecal administration of EphB2-Fc in the TNBS + EphB2-Fc group. The number of EphB1- and p-EphB1-immunopositive cells, the average optical (AO) value of EphB1, and its phosphorylated form in the spinal dorsal horn were significantly increased in the TNBS group than in the control group, but they were obviously reduced by intrathecal administration of EphB2-Fc. There were no significant differences in the number of ephrinB2- and p-ephrinB2-immunopositive cells and the AO value of ephrinB2 and its phosphorylated form between the TNBS and TNBS + EphB2-Fc groups. Conclusion. EphB1 receptors in the spinal dorsal horn play a pivotal role in the development of visceral pain and may be considered as a potential target for the treatment of visceral pain.

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