Propofol Alleviates Neuropathic Pain Induced by Chronic Contractile Injury by Regulating the Spinal glun2b-p38mapkepac1 Pathway

Background. Propofol acts as an intravenous anesthetic cure which is widely used as a therapy for the craniocerebral injury that comprised surgical anesthesia as well as the sedation done in the intensive care units. Propofol is one of the most commonly used and efficient anesthetics where the painful effects are followed by an injection of propofol. In many cases, patients experience pain followed by anxiety, boredom, fear, and even myocardial ischemia. Objective. This study was performed to investigate the underlying mechanism of propofol and its effect on regulating spinal glun2b-p38mapkepac1 pathways in chronic contractile injury. Material and Methods. Contractile injury was performed by ligation around the nerve of the thigh region postanesthesia. Rats were divided into three groups to analyze the changes like mechanical allodynia by the paw withdrawal threshold and histopathological analysis for assessing cellular degradation. L4-L6 from the spinal dorsal horns were isolated and harvested for studying protein expression, by the method of western blotting and immunofluorescence analysis. Results. The pain caused due to mechanical allodynia in the paw region was highest at 1 hour postinduction and lasted for three days postinjury. Pain was significantly less in the group receiving propofol when compared with the isoflurane group for the first two hours of injury. In the propofol group, EPAC1, GluN2B, and p38 MAP K were significantly lower. Conclusion. In the rat model of induced chronic contractile injury, postsurgery there was a suppression of the GluN2B-p38MAPK/EPAC1 signaling pathway in the propofol group. As the p38MAPK/EPAC pathway has a significant role in the postoperative hyperalgesia, thus our experiment suggests that propofol has analgesic effects.

Download Full-text

Dexmedetomidine Alleviates Hyperalgesia in Arthritis Rats Through Inhibition of the p38MAPK Signaling Pathway

10.21203/rs.3.rs-1049464/v1 ◽

2021 ◽

Author(s):

Bin Nie ◽

Hui Jiang ◽

Hong Chen ◽

Qiong Liu

Keyword(s):

Signaling Pathway ◽

Rat Model ◽

Underlying Mechanism ◽

Inflammatory Factors ◽

Pathological Changes ◽

Related Factors ◽

Withdrawal Threshold ◽

Analgesic Effects ◽

Joint Cavity ◽

P38mapk Signaling

Abstract Background: Dexmedetomidine (DEX) has showed significant analgesic effects in neuropathic pain, but the underlying mechanism has remained elusive. Our present study aimed to explore the effect of DEX on hyperalgesia with the involvement of p38MAPK signaling pathway a rat model of monoarthritis (MA).Methods: MA rat model was induced by injection of Complete Freund's Adjuvant (CFA). Pathological changes of ma rats were observed by HE staining and Safranin-O/Fast Green staining. Ankle circumference, paw withdrawal latency (PWL) and paw withdrawal threshold (PWT) was measured to judge the degree of hyperalgesia in MA rats. Immunohistochemistry and ELISA were applied to observe the degree of inflammation in rats. Western blot analysis was conducted to detect expression of p38MAPK signaling pathway-related factors. The mechanism of p38MAPK signaling pathway in MA rats was observed via treatment of Anisomycin or SB203580 combined with DEX.Results: After 8 h of CFA induction, joint swelling and hyperalgesia occurred in rats. There were obvious pathological changes in the joint cavity, the joint cavity space became narrow and synovial bursa became rough. A large number of inflammatory cell infiltration was observed under microscope. After injection of DEX and SB203580, PWT and PWL was prolonged, the expression of serum inflammatory factors was decreased, and the expression of p38MAPK signaling pathway-related factors was decreased; while all the detected indexes were recovered in MA rats after treated with DEX and Anisomycin.Conclusions: Our study provided evidence that DEX could alleviate hyperalgesia in arthritis rats through inhibition of the p38MAPK signaling pathway.

Download Full-text

IL4-10 Fusion Protein Shows DMOAD Activity in a Rat Osteoarthritis Model

Cartilage ◽

10.1177/19476035211026736 ◽

2021 ◽

pp. 194760352110267

Author(s):

E.M. van Helvoort ◽

H.M. de Visser ◽

F.P.J.G. Lafeber ◽

K. Coeleveld ◽

S. Versteeg ◽

...

Keyword(s):

Fusion Protein ◽

Single Molecule ◽

Mechanical Allodynia ◽

Cartilage Damage ◽

Cartilage Degeneration ◽

Synovial Inflammation ◽

Interleukin 4 ◽

Analgesic Effects ◽

Metabolic Dysregulation ◽

Anti Inflammatory

Objective Ideally, disease-modifying osteoarthritis (OA) drugs (DMOAD) should combine chondroprotective, anti-inflammatory, and analgesic effects in a single molecule. A fusion protein of interleukin-4 (IL-4) and IL-10 (IL4-10 FP) possesses these combined effects. In this study, the DMOAD activity of rat IL4-10 FP (rIL4-10 FP) was tested in a rat model of surgically induced OA under metabolic dysregulation. Design rIL4-10 FP was produced with HEK293F cells. Bioactivity of purified rIL4-10 FP was determined in a whole blood assay. Male Wistar rats ( n = 20) were fed a high-fat diet (HFD) to induce metabolic dysregulation. After 12 weeks, OA was induced according to the Groove model. Two weeks after OA induction, rats were randomly divided into 2 groups and treated with 10 weekly, intra-articular injections of either rIL4-10 FP ( n = 10) or phosphate buffered saline (PBS; n = 10). Possible antibody formation was evaluated using ELISA, cartilage degeneration and synovial inflammation were evaluated by histology and mechanical allodynia was evaluated using the von Frey test. Results Intra-articular injections with rIL4-10 FP significantly reduced cartilage degeneration ( P = 0.042) and decreased mechanical allodynia ( P < 0.001) compared with PBS. Only mild synovial inflammation was found (nonsignificant), limiting detection of putative anti-inflammatory effects. Multiple injections of rIL4-10 FP did not induce antibodies against rIL4-10 FP. Conclusion rIL4-10 FP showed chondroprotective and analgesic activity in a rat OA model with moderate cartilage damage, mild synovial inflammation, and pain. Future studies will need to address whether less frequent intra-articular injections, for example, with formulations with increased residence time, would also lead to DMOAD activity.

Download Full-text

PRC1 promotes GLI1-dependent osteopontin expression in association with the Wnt/β-catenin signaling pathway and aggravates liver fibrosis

Cell & Bioscience ◽

10.1186/s13578-019-0363-2 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Shenzong Rao ◽

Jie Xiang ◽

Jingsong Huang ◽

Shangang Zhang ◽

Min Zhang ◽

...

Keyword(s):

Liver Fibrosis ◽

Western Blot ◽

Cell Viability ◽

Signaling Pathway ◽

Cell Model ◽

Stellate Cell ◽

Underlying Mechanism ◽

Histopathological Analysis ◽

Osteopontin Expression

Abstract Background PRC1 (Protein regulator of cytokinesis 1) regulates microtubules organization and functions as a novel regulator in Wnt/β-catenin signaling pathway. Wnt/β-catenin is involved in development of liver fibrosis (LF). We aim to investigate effect and mechanism of PRC1 on liver fibrosis. Methods Carbon tetrachloride (CCl4)-induced mice LF model was established and in vitro cell model for LF was induced by mice primary hepatic stellate cell (HSC) under glucose treatment. The expression of PRC1 in mice and cell LF models was examined by qRT-PCR (quantitative real-time polymerase chain reaction), western blot and immunohistochemistry. MTT assay was used to detect cell viability, and western blot to determine the underlying mechanism. The effect of PRC1 on liver pathology was examined via measurement of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and hydroxyproline, as well as histopathological analysis. Results PRC1 was up-regulated in CCl4-induced mice LF model and activated HSC. Knockdown of PRC1 inhibited cell viability and promoted cell apoptosis of activated HSC. PRC1 expression was regulated by Wnt3a signaling, and PRC1 could regulate downstream β-catenin activation. Moreover, PRC1 could activate glioma-associated oncogene homolog 1 (GLI1)-dependent osteopontin expression to participate in LF. Adenovirus-mediated knockdown of PRC1 in liver attenuated LF and reduced collagen deposition. Conclusions PRC1 aggravated LF through regulating Wnt/β-catenin mediated GLI1-dependent osteopontin expression, providing a new potential therapeutic target for LF treatment.

Download Full-text

Analgesic Effects of Cnidium officinale Extracts on Postoperative, Neuropathic, and Menopausal Pain in Rat Models

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/9698727 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Eun Yeong Lim ◽

Jae Goo Kim ◽

Jaekwang Lee ◽

Changho Lee ◽

Jaewon Shim ◽

...

Keyword(s):

Ferulic Acid ◽

Dorsal Root Ganglion Neurons ◽

Great Efficacy ◽

Withdrawal Threshold ◽

Analgesic Effects ◽

Pain Models ◽

Cnidium Officinale ◽

Model Treatment ◽

Ganglion Neurons

Cnidium officinale, widely cultivated in East Asia, has been reported to exhibit pharmacological efficacy in various disorders. However, little has been reported on its role as a pain killer. In this study, we reveal that the C. officinale extract (COE) has great efficacy as a novel analgesic in various in vivo pain models. Administration of COE attenuated hypersensitivity in all postoperative, neuropathic, and menopausal pain models. Decreased hyperalgesia was confirmed by a mechanical withdrawal threshold assay and ultrasonic vocalization call analysis. In addition, application of COE inhibited the induction of the proinflammatory cytokines and calpain-3 on dorsal root ganglion neurons in a spared nerve injury rat model. Treatment with ferulic acid, which was identified as one of the components of COE by HPLC analysis, alleviated nociceptive behaviors. Our findings suggest that ferulic acid is an active compound from COE, and COE is a potential phytomedical source for pain relief by inhibiting the process of inflammation.

Download Full-text

Levo-Tetrahydropalmatine Attenuates Bone Cancer Pain by Inhibiting Microglial Cells Activation

Mediators of Inflammation ◽

10.1155/2015/752512 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 9

Author(s):

Mao-yin Zhang ◽

Yue-peng Liu ◽

Lian-yi Zhang ◽

Dong-mei Yue ◽

Dun-yi Qi ◽

...

Keyword(s):

Spinal Cord ◽

Cancer Pain ◽

Mechanical Allodynia ◽

Thermal Hyperalgesia ◽

Bone Cancer ◽

Microglial Cells ◽

Bone Cancer Pain ◽

Enzyme Linked Immunosorbent Assay ◽

Analgesic Effects ◽

Before And After

Objective. The present study is to investigate the analgesic roles of L-THP in rats with bone cancer pain caused by tumor cell implantation (TCI).Methods. Thermal hyperalgesia and mechanical allodynia were measured at different time points before and after operation. L-THP (20, 40, and 60 mg/kg) were administrated intragastrically at early phase of postoperation (before pain appearance) and later phase of postoperation (after pain appearance), respectively. The concentrations of TNF-α, IL-1β, and IL-18 in spinal cord were measured by enzyme-linked immunosorbent assay. Western blot was used to test the activation of astrocytes and microglial cells in spinal cord after TCI treatment.Results. TCI treatment induced significant thermal hyperalgesia and mechanical allodynia. Administration of L-THP at high doses significantly prevented and/or reversed bone cancer-related pain behaviors. Besides, TCI-induced activation of microglial cells and the increased levels of TNF-αand IL-18 were inhibited by L-THP administration. However, L-THP failed to affect TCI-induced astrocytes activation and IL-1βincrease.Conclusion. This study suggests the possible clinical utility of L-THP in the treatment of bone cancer pain. The analgesic effects of L-THP on bone cancer pain maybe underlying the inhibition of microglial cells activation and proinflammatory cytokines increase.

Download Full-text

Unusual olfactory perception during radiation sessions for primary brain tumors: a retrospective study

Journal of Radiation Research ◽

10.1093/jrr/rrz060 ◽

2019 ◽

Vol 60 (6) ◽

pp. 812-817

Author(s):

Mika Obinata ◽

Kana Yamada ◽

Keisuke Sasai

Keyword(s):

Brain Tumors ◽

Total Population ◽

Radiation Treatment ◽

Germ Cell Tumors ◽

Internal Standard ◽

Underlying Mechanism ◽

Primary Brain Tumors ◽

Medical Study ◽

Number Of Patients ◽

Patients Experience

Abstract During irradiation sessions for brain tumors or head and neck cancers, some patients experience abnormal olfactory sensations. To date, the frequency of such sensations during these treatment sessions has not been investigated. We analyzed abnormal olfactory sensations in patients who underwent radiation therapy at our institution for primary brain tumors, excluding malignant lymphoma, between January 2009 and January 2018. A total of 191 patients who were awake during radiation treatment and capable of communicating were analyzed in this retrospective medical study. Of these patients, 7 were aware of olfactory sensations during irradiation. The median age of these 7 patients was 13 (range 8–47) years, Six were <20 years of age, accounting for 10% of the total population of similar age (n = 60). However, only 1 of 131 patients aged ≥20 years complained of strange olfactory sensations. Four of seven patients had germ cell tumors, but none had a medulloblastoma. We investigated patients who experienced light sensation, as an internal standard to ascertain the accuracy of this study. Only 10 patients experienced light sensation during their irradiation sessions. This suggests that the frequency of these sensations was possibly underestimated in our study. In conclusion, a considerable number of patients experienced unusual olfactory sensations during radiation treatment. Further prospective studies on abnormal olfactory sensations during irradiation are needed to clarify the underlying mechanism of this sensation.

Download Full-text

Electroacupuncture Treatment Alleviates Central Poststroke Pain by Inhibiting Brain Neuronal Apoptosis and Aberrant Astrocyte Activation

Neural Plasticity ◽

10.1155/2016/1437148 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 8

Author(s):

Gui-Hua Tian ◽

Shan-Shan Tao ◽

Man-Tang Chen ◽

Yu-Sang Li ◽

You-Ping Li ◽

...

Keyword(s):

Neuronal Apoptosis ◽

Signal Transmission ◽

Low Frequency ◽

Underlying Mechanism ◽

Tunel Staining ◽

Astrocyte Activation ◽

Related Factors ◽

Nissl Staining ◽

Analgesic Effects ◽

Cox 2

Electroacupuncture (EA) is reported to effectively relieve the central poststroke pain (CPSP). However, the underlying mechanism remains unclear. The present study investigated the detailed mechanisms of action of EA treatment at different frequencies for CPSP. A CPSP model was established with a single collagenase injection to the left ventral posterolateral nucleus of the thalamus. The EA-treated groups then received EA treatment at frequency of 2, 2/15, or 15 Hz for 30 min daily for five days. The pain-related behavioral responses, neuronal apoptosis, glial activation, and the expression of pain signal transmission-related factors (β-catenin, COX-2, and NK-1R) were assessed using behavioral tests, Nissl staining, TUNEL staining, and immunohistochemical staining, respectively. The low-frequency EA treatment significantly (1) reduced brain tissue damage and hematoma sizes and (2) inhibited neuronal apoptosis, thereby exerting abirritative effects. Meanwhile, the high-frequency EA treatment induced a greater inhibition of the aberrant astrocyte activation, accompanied by the downregulation of the expressions of COX-2,β-catenin, and subsequently NK-1R, thereby alleviating inflammation and producing strong analgesic effects. Together, these findings suggest that CPSP is closely related to pathological changes of the neocortex and hippocampus. EA treatments at different frequencies may exert abirritative effects by inhibiting brain neuronal apoptosis and aberrant astrocyte activation in the brain.

Download Full-text

Expression of transcription factors in MEN1-associated pancreatic neuroendocrine tumors

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-17-0088 ◽

2017 ◽

Vol 2017 ◽

Author(s):

Yasutaka Takeda ◽

Yukihiro Fujita ◽

Kentaro Sakai ◽

Tomoe Abe ◽

Tomonobu Nakamura ◽

...

Keyword(s):

Transcription Factors ◽

Cell Differentiation ◽

Neuroendocrine Tumors ◽

Immunohistochemical Analysis ◽

Underlying Mechanism ◽

Histopathological Analysis ◽

List Type ◽

Pancreatic Neuroendocrine Tumors ◽

Hormone Production ◽

Head Of The Pancreas

Summary MEN1-associated pancreatic neuroendocrine tumors (pNETs) may potentially express distinct hormones, but the mechanism has not been elucidated. Transcription factors such as MafA and Pdx1 have been identified to lead to beta cell differentiation, while Arx and Brn4 to alpha cell differentiation in developing pancreas. We hypothesized those transcription factors are important to produce specific hormones in pNETs, similarly to developing pancreas, and examined the expression of transcription factors in a case of MEN1 who showed immunohistological coexistence of several hormone-producing pNETs including insulinoma. A 70-year-old woman was found to manifest hypoglycemia with non-suppressed insulinemia and hypercalcemia with elevated PTH level. She was diagnosed as MEN1 based on the manifestation of primary hyperparathyroidism, pituitary adenoma and insulinoma, with genetic variation of MEN1 gene. She had pylorus-preserving pancreaticoduodenectomy because CT scan and SACI test indicated that insulinoma was localized in the head of the pancreas. Histopathological finding was MEN1-associated NET, G1. Interestingly, immunohistological examination of the resected pancreas revealed that two insulinomas, a glucagon-positive NET and a multiple hormone-positive NET coexisted. Hence, we examined the expression of transcription factors immunohistochemically to elucidate the role of the transcription factors in MEN1-associated hormone-producing pNETs. We observed homogeneous expressions of MafA and Pdx1 in insulinomas and Arx in glucagon-positive NET, respectively. Moreover, multiple hormone-positive NETs expressed several transcription factors heterogeneously. Collectively, our results suggested that transcription factors could play important roles in the production of specific hormones in MEN1-associated pNETs, similar to islet differentiation. Learning points: To date, it has been shown that different hormone-producing tumors coexist in MEN1-associated pNETs; however, the underlying mechanism of the hormone production in MEN1-associated pNETs has not been well elucidated. Although this case presented symptomatic hypoglycemia, several hormone-producing pNETs other than insulinoma also coexisted in the pancreas. Immunohistochemical analysis showed MafA and Pdx1 expressions distinctly in insulinoma, and Arx expression particularly in a glucagon-positive NET, while a multiple hormone-positive NET expressed MafA, Pdx1 and Arx. Collectively, clinicians should consider that several hormone-producing pNETs may coexist in a MEN1 case and examine both endocrinological and histopathological analysis of pNETs, regardless of whether symptoms related to the excess of hormones are observed or not.

Download Full-text

The Role of Toll-Like Receptor 4 Mediates Microglial Activation during Remifentanil-Induced Hyperalgesia in Rats

10.21203/rs.2.73/v1 ◽

2018 ◽

Author(s):

Xiang Xiang Chen ◽

Xin Wei

Keyword(s):

Mechanical Allodynia ◽

Microglial Activation ◽

Cell Activation ◽

Thermal Hyperalgesia ◽

Toll Like Receptor ◽

Sprague Dawley ◽

Toll Like Receptor 4 ◽

Withdrawal Threshold ◽

Incisional Pain

Abstract Background: Opioids can induce a state of nociceptive sensitization, also known as opioid-induced hyperalgesia. Nevertheless, the exact mechanism is still unclear. The following study investigates the role of Toll-like receptor 4 (TLR4) in the microglial activation during remifentanil—induced hyperalgesia in rats’ model of incisional pain. Methods: Mechanical allodynia induced by remifentanil was established in adult male Sprague–Dawley rats with incisional pain. Paw withdrawal threshold (PWT) and paw withdrawal thermal latency (PWTL) were performed to evaluate mechanical and thermal hyperalgesia. The 32-G catheter intrathecal placement was used to deliver a specific TLR4 antagonist (LPS-RS).Western blot analysis was performed to measure the expression of the TLR4 and iba-1, while Immunoﬂuorescence staining was used to investigate the cell type and cell activation. Results：Incisionalpain-remifentanil decreased the PWT and PWTL, upregulated the expression of TLR4 and microglial activation in the spinal cord. On the contrary, the intrathecal delivery of LPS-RS at the dose of 25 μg significantly decreased mechanical allodynia and prevented the upregulation of TLR4 induced by incisional pain-remifentanil Conclusion: These findings suggest that TLR4 signaling pathway has an important role in incisional pain-remifentanil hyperalgesia, and that it could serve as the therapeutic target for persistent postsurgical pain

Download Full-text

The Role of Toll-Like Receptor 4 Mediates Microglial Activation during Remifentanil-Induced Hyperalgesia in Rats

10.21203/rs.2.73/v2 ◽

2019 ◽

Author(s):

xiangxiang chen ◽

Xin Wei

Keyword(s):

Mechanical Allodynia ◽

Cell Activation ◽

Thermal Hyperalgesia ◽

Microglia Activation ◽

Toll Like Receptor ◽

Sprague Dawley ◽

Toll Like Receptor 4 ◽

Withdrawal Threshold ◽

Incisional Pain

Abstract Background: Opioids can induce a state of nociceptive sensitization, also known as opioid-induced hyperalgesia. Nevertheless, the exact mechanism is still unclear. The following study investigates the role of Toll-like receptor 4 (TLR4) in the microglia activation during remifentanil—induced hyperalgesia in rats’ model of incisional pain. Methods: Mechanical allodynia induced by remifentanil was established in adult male Sprague–Dawley rats with incisional pain. Paw withdrawal threshold (PWT) and paw withdrawal thermal latency (PWTL) were performed to evaluate mechanical and thermal hyperalgesia. The 32-G catheter intrathecal placement was used to deliver a specific TLR4 antagonist (LPS-RS).Western blot analysis was performed to measure the expression of the TLR4 and Iba-1, while Immunoﬂuorescence staining was used to investigate the cell type and cell activation. Results：Incisionalpain-remifentanil decreased the PWT and PWTL, upregulated the expression of TLR4 and microglia activation in the spinal cord. On the contrary, the intrathecal delivery of LPS-RS at the dose of 25 μg significantly decreased mechanical allodynia and prevented the upregulation of TLR4 induced by incisional pain-remifentanil Conclusion: These findings suggest that TLR4 signaling pathway has an important role in incisional pain-remifentanil hyperalgesia, and that it could serve as the therapeutic target for persistent postsurgical pain

Download Full-text