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Liu S, Zhu R, Zhang Y, Jiang Z, Chen Y, Song Q, Wang F. Targeting PI3K-mTOR signaling in the anterior cingulate cortex improves emotional behavior, and locomotor activity in rats with bone cancer pain. Ann Med Surg (Lond) 2025; 87:1985-1994. [PMID: 40212145 PMCID: PMC11981390 DOI: 10.1097/ms9.0000000000003206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 03/09/2025] [Indexed: 04/13/2025] Open
Abstract
Objective To investigate the effects of targeting the PI3K-mTOR signaling pathway in the anterior cingulate cortex (ACC) on pain responses, locomotor activity, and emotional behavior in rats with bone cancer pain. Methods Bone cancer pain was induced by implanting Walker 256 cells into the rat. Pain responses were assessed using paw withdrawal threshold and latency measurements, while locomotor activity and negative mood were evaluated through open field and conditioned place aversion tests, respectively. Results The results showed that the bone cancer pain model led to allodynia, hyperalgesia, decreased ambulation, and ACC microglial activation. Morphine treatment improved pain responses but did not affect locomotor activity or mTOR protein expression. In contrast, rapamycin treatment reduced pain, improved locomotor activity, and decreased negative mood. It also downregulated PI3K-mTOR protein expression. Furthermore, inhibiting the PI3K-mTOR pathway with a PI3K inhibitor or rapamycin not only improved pain responses and locomotor activity but also reduced depression and anxiety-like behaviors. These effects were accompanied by changes in paw withdrawal threshold, latency, static time, and PI3K-mTOR protein expression. Conclusions Targeting the PI3K-mTOR signaling pathway in the ACC effectively alleviates pain-related symptoms and emotional disturbances in rats with bone cancer pain. This approach holds promise for alleviating pain and allaying negative emotion after further study.
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Affiliation(s)
- Shuyun Liu
- Department of Anesthesiology, Shaoxing People’s Hospital, Shaoxing, China
| | - Rujia Zhu
- School of Medicine, Shaoxing University, Shaoxing, China
| | - Yuan Zhang
- Department of Anesthesiology, Shaoxing People’s Hospital, Shaoxing, China
| | - Zongming Jiang
- Department of Anesthesiology, Shaoxing People’s Hospital, Shaoxing, China
| | - Yonghao Chen
- Department of Anesthesiology, Shanghai Jiang Qiao Hospital, Shanghai, China
| | - Qiliang Song
- Department of Anesthesiology, Shaoxing People’s Hospital, Shaoxing, China
| | - Fei Wang
- Bioinformation Branch, Hangzhou Hibio Bioinformation Technology Company, HangZhou, China
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Zhang K, Ran R, Zhang CJ, Wang L, Zhang HH. Focus on P2X7R in microglia: its mechanism of action and therapeutic prospects in various neuropathic pain models. Front Pharmacol 2025; 16:1555732. [PMID: 40201695 PMCID: PMC11975881 DOI: 10.3389/fphar.2025.1555732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 03/07/2025] [Indexed: 04/10/2025] Open
Abstract
Neuropathic pain (NP) is a common symptom of many diseases and is caused by direct or indirect damage to the nervous system. Tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors are typical drugs used in clinical practice to suppress pain. However, these drugs have drawbacks, including a short duration of action, a limited analgesic effect, and possible dependence and side effects. Therefore, developing more effective NP treatment strategies has become a priority in medical research and has attracted much research attention. P2X7 receptor (P2X7R) is a non-selective cation channel activated by adenosine triphosphate and is mainly expressed in microglia in the central nervous system. Microglial P2X7R plays an important role in pain regulation, suggesting that it could be a potential target for drug development. This review comprehensively and objectively discussed the latest research progress of P2X7R, including its structural characteristics, functional properties, relationship with microglial activation and polarization, mechanism of action, and potential therapeutic strategies in multiple NP models. This study aimed to provide in-depth insights into the association between P2X7R and NP and explore the mechanism of action of P2X7R in the pathological process of NP and the translational potential and clinical application prospects of P2X7R antagonists in pain treatment, providing a scientific basis for the precise treatment of NP.
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Affiliation(s)
- Kai Zhang
- Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou, China
- Orthopedics Key Laboratory of Gansu Province, Lanzhou, China
| | - Rui Ran
- Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou, China
- Orthopedics Key Laboratory of Gansu Province, Lanzhou, China
| | | | - Linna Wang
- Lanzhou Biotechnique Development Co., Ltd., Lanzhou, China
| | - Hai-Hong Zhang
- Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou, China
- Orthopedics Key Laboratory of Gansu Province, Lanzhou, China
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Xu JP, Ouyang QW, Shao MJ, Ke H, Du H, Xu SC, Yang Q, Cui YR, Qu F. Manual acupuncture ameliorates inflammatory pain by upregulating adenosine A 3 receptor in complete Freund's adjuvant-induced arthritis rats. Int Immunopharmacol 2024; 133:112095. [PMID: 38678668 DOI: 10.1016/j.intimp.2024.112095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 04/06/2024] [Accepted: 04/12/2024] [Indexed: 05/01/2024]
Abstract
BACKGROUND Adenosine A3 receptor (A3R) exerts analgesic, anti-inflammatory, and anti-nociceptive effects. In this study, we determined the analgesic mechanism of manual acupuncture (MA) in rats with complete Freund's adjuvant (CFA)-induced arthritis and explored whether MA ameliorates inflammation in these rats by upregulating A3R. METHODS Sixty Sprague Dawley (SD) rats were randomly divided into the following groups: Control, CFA, CFA + MA, CFA + sham MA, CFA + MA + DMSO, CFA + MA + IB-MECA, and CFA + MA + Reversine groups. The arthritis rat model was induced by injecting CFA into the left ankle joints. Thereafter, the rats were subjected to MA (ST36 acupoint) for 3 days. The clinical indicators paw withdrawal latency (PWL), paw withdrawal threshold (PWT), and open field test (OFT) were used to determine the analgesic effect of MA. In addition, to explore the effect of A3R on inflammation after subjecting arthritis rats to MA, IB-MECA (A3R agonist) and Reversine (A3R antagonist) were injected into ST36 before MA. RESULTS MA ameliorated the pathological symptoms of CFA-induced arthritis, including the pain indicators PWL and PWT, number of rearing, total ambulatory distance, and activity trajectory. Furthermore, after MA, the mRNA and protein expression of A3R was upregulated in CFA-induced arthritis rats. In contrast, the protein levels of TNF-α, IL-1β, Rap1, and p-p65 were downregulated after MA. Interestingly, the A3R agonist and antagonist further downregulated and upregulated inflammatory cytokine expression, respectively, after MA. Furthermore, the A3R antagonist increased the degree of ankle swelling after MA. CONCLUSION MA can alleviate inflammatory pain by inhibiting the NF-κB signaling pathway via upregulating A3R expression of the superficial fascia of the ST36 acupoint site in CFA-induced arthritis rats.
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Affiliation(s)
- Jing-Ping Xu
- Department of Physiology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330004, China
| | - Qian-Wen Ouyang
- Nanchang People's Hospital, Jiangxi Province Key Laboratory for Breast Diseases, Nanchang, Jiangxi 334000, China
| | - Mei-Juan Shao
- Department of Pharmacology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330004, China
| | - Hong Ke
- Department of Physiology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330004, China
| | - Hong Du
- Department of Pharmacology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330004, China
| | - Shang-Cheng Xu
- Department of Pharmacology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330004, China
| | - Qian Yang
- Department of Pharmacology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330004, China
| | - Yan-Ru Cui
- Department of Physiology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330004, China.
| | - Fei Qu
- Department of Pharmacology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330004, China.
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Wang J, Song W, Zhang Y, Wang J, Wang Y, Song J, Zhou Y. Electroacupuncture Alleviates Pain by Suppressing P2Y12R-Dependent Microglial Activation in Monoarthritic Rats. Neurochem Res 2024; 49:1268-1277. [PMID: 38337134 DOI: 10.1007/s11064-024-04114-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 11/13/2023] [Accepted: 01/23/2024] [Indexed: 02/12/2024]
Abstract
Electroacupuncture (EA) effectively improves arthritis-induced hyperalgesia and allodynia by repressing spinal microglial activation, which plays a crucial role in pain hypersensitivity following tissue inflammation. However, the mechanism by which EA suppresses spinal microglial activation in monoarthritis (MA) remains unclear. In the present study, a rat model of MA was established through unilateral ankle intra-articular injection of complete Freund's adjuvant (CFA). The relationship among P2Y12 receptor (P2Y12R) expression, spinal microglial activation, and EA analgesia was investigated using quantitative real-time PCR (qRT‒PCR), western blotting, immunofluorescence (IF), and behavioral testing. The results found that EA treatment at the ipsilateral "Huantiao" (GB30) and "Yanglingquan" (GB34) acupoints markedly attenuated pain and spinal microglia M1 polarization in MA rats. In particular, P2Y12R expression was significantly increased at the mRNA and protein levels in the spinal dorsal horn in MA rats, whereas EA treatment effectively repressed the MA-induced upregulation of P2Y12R. IF analysis further revealed that most P2Y12R was expressed in microglia in the spinal dorsal horn. Pharmacological inhibition of P2Y12R by its antagonist (AR-C69931MX) decreased MA-induced spinal microglial activation and subsequent proinflammatory cytokine production. Consequently, AR-C69931MX significantly intensified the anti-pain hypersensitive function of EA in MA rats. Taken together, these results demonstrate that EA alleviates MA-induced pain by suppressing P2Y12R-dependent microglial activation.
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Affiliation(s)
- Jing Wang
- Department of Anesthesiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 185, Pu An Road, Shanghai, 201203, China
| | - Wei Song
- Department of Anesthesiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 185, Pu An Road, Shanghai, 201203, China
| | - Yujiao Zhang
- Department of Anesthesiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 185, Pu An Road, Shanghai, 201203, China
| | - Jian Wang
- Department of Anesthesiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 185, Pu An Road, Shanghai, 201203, China
| | - Yongqiang Wang
- Department of Anesthesiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 185, Pu An Road, Shanghai, 201203, China
| | - Jiangang Song
- Department of Anesthesiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 185, Pu An Road, Shanghai, 201203, China.
| | - Yalan Zhou
- Department of Anesthesiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 185, Pu An Road, Shanghai, 201203, China.
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Zhang R, Wang J, Deng Q, Xiao X, Zeng X, Lai B, Li G, Ma Y, Ruan J, Han I, Zeng YS, Ding Y. Mesenchymal Stem Cells Combined With Electroacupuncture Treatment Regulate the Subpopulation of Macrophages and Astrocytes to Facilitate Axonal Regeneration in Transected Spinal Cord. Neurospine 2023; 20:1358-1379. [PMID: 38171303 PMCID: PMC10762392 DOI: 10.14245/ns.2346824.412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/21/2023] [Accepted: 09/25/2023] [Indexed: 01/05/2024] Open
Abstract
OBJECTIVE Herein, we investigated whether mesenchymal stem cells (MSCs) transplantation combined with electroacupuncture (EA) treatment could decrease the proportion of proinflammatory microglia/macrophages and neurotoxic A1 reactive astrocytes and inhibit glial scar formation to enhance axonal regeneration after spinal cord injury (SCI). METHODS Adult rats were divided into 5 groups after complete transection of the spinal cord at the T10 level: a control group, a nonacupoint EA (NA-EA) group, an EA group, an MSC group, and an MSCs+EA group. Immunofluorescence labeling, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blots were performed. RESULTS The results showed that MSCs+EA treatment reduced the proportion of proinflammatory M1 subtype microglia/macrophages, but increased the differentiation of anti-inflammatory M2 phenotype cells, thereby suppressing the mRNA and protein expression of proinflammatory cytokines (tumor necrosis factor-α and IL-1β) and increasing the expression of an anti-inflammatory cytokine (interleukin [IL]-10) on days 7 and 14 after SCI. The changes in expression correlated with the attenuated neurotoxic A1 reactive astrocytes and glial scar, which in turn facilitated the axonal regeneration of the injured spinal cord. In vitro, the proinflammatory cytokines increased the level of proliferation of astrocytes and increased the expression levels of C3, glial fibrillary acidic protein, and chondroitin sulfate proteoglycan. These effects were blocked by administering inhibitors of ErbB1 and signal transducer and activator of transcription 3 (STAT3) (AG1478 and AG490) and IL-10. CONCLUSION These findings showed that MSCs+EA treatment synergistically regulated the microglia/macrophage subpopulation to reduce inflammation, the formation of neurotoxic A1 astrocytes, and glial scars. This was achieved by downregulating the ErbB1-STAT3 signal pathway, thereby providing a favorable microenvironment conducive to axonal regeneration after SCI.
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Affiliation(s)
- Rongyi Zhang
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Department of Pain Management, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Junhua Wang
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Qingwen Deng
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xingru Xiao
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Key Laboratory for Stem Cells and Tissue Engineering Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Xiang Zeng
- Key Laboratory for Stem Cells and Tissue Engineering Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Biqin Lai
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Key Laboratory for Stem Cells and Tissue Engineering Ministry of Education, Sun Yat-sen University, Guangzhou, China
- Institute of Spinal Cord Injury, Sun Yat-sen University, Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Ge Li
- Key Laboratory for Stem Cells and Tissue Engineering Ministry of Education, Sun Yat-sen University, Guangzhou, China
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Science, Guangzhou, China
| | - Yuanhuan Ma
- Key Laboratory for Stem Cells and Tissue Engineering Ministry of Education, Sun Yat-sen University, Guangzhou, China
- Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, South China University of Technology, Guangzhou, China
| | - Jingwen Ruan
- Department of Acupuncture, the 1st Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Inbo Han
- Department of Neurosurgery, Bundang CHA Medical Center, CHA University College of Medicine, Seongnam, Korea
| | - Yuan-Shan Zeng
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Key Laboratory for Stem Cells and Tissue Engineering Ministry of Education, Sun Yat-sen University, Guangzhou, China
- Institute of Spinal Cord Injury, Sun Yat-sen University, Sun Yat-sen Memorial Hospital, Guangzhou, China
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Ying Ding
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Key Laboratory for Stem Cells and Tissue Engineering Ministry of Education, Sun Yat-sen University, Guangzhou, China
- Institute of Spinal Cord Injury, Sun Yat-sen University, Sun Yat-sen Memorial Hospital, Guangzhou, China
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Hu L, Yang J, Liu T, Zhang J, Huang X, Yu H. Hotspots and Trends in Research on Treating Pain with Electroacupuncture: A Bibliometric and Visualization Analysis from 1994 to 2022. J Pain Res 2023; 16:3673-3691. [PMID: 37942222 PMCID: PMC10629439 DOI: 10.2147/jpr.s422614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 10/19/2023] [Indexed: 11/10/2023] Open
Abstract
Purpose Electroacupuncture is widely used to pain management. A bibliometric analysis was conducted to identify the hotspots and trends in research on electroacupuncture for pain. Methods We retrieved studies published from 1994-2022 on the topic of pain relief by electroacupuncture from the Web of Science Core Collection database. We comprehensively analysed the data with VOSviewer, CiteSpace, and bibliometrix. Seven aspects of the data were analysed separately: annual publication outputs, countries, institutions, authors, journals, keywords and references. Results A total of 2030 papers were analysed, and the number of worldwide publications continuously increased over the period of interest. The most productive country and institution in this field were China and KyungHee University. Evidence-Based Complementary and Alternative Medicine was the most productive journal, and Pain was the most co-cited journal. Han Jisheng, Fang Jianqiao, and Lao Lixing were the most representative authors. Based on keywords and references, three active areas of research on EA for pain were mechanisms, randomized controlled trials, and perioperative applications. Three emerging trends were functional magnetic resonance imaging (fMRI), systematic reviews, and knee osteoarthritis. Conclusion This study comprehensively analysed the research published over the past 28 years on electroacupuncture for pain treatment, using bibliometrics and science mapping analysis. This work presents the current status and landscape of the field and may serve as a valuable resource for researchers. Chronic pain, fMRI-based mechanistic research, and the perioperative application of electroacupuncture are among the likely foci of future research in this area.
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Affiliation(s)
- Liyu Hu
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
| | - Jikang Yang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
| | - Ting Liu
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
| | - Jinhuan Zhang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
| | - Xingxian Huang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
| | - Haibo Yu
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
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Yang Y, Rao C, Yin T, Wang S, Shi H, Yan X, Zhang L, Meng X, Gu W, Du Y, Hong F. Application and underlying mechanism of acupuncture for the nerve repair after peripheral nerve injury: remodeling of nerve system. Front Cell Neurosci 2023; 17:1253438. [PMID: 37941605 PMCID: PMC10627933 DOI: 10.3389/fncel.2023.1253438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 10/09/2023] [Indexed: 11/10/2023] Open
Abstract
Peripheral nerve injury (PNI) is a structural event with harmful consequences worldwide. Due to the limited intrinsic regenerative capacity of the peripheral nerve in adults, neural restoration after PNI is difficult. Neurological remodeling has a crucial effect on the repair of the form and function during the regeneration of the peripheral nerve after the peripheral nerve is injured. Several studies have demonstrated that acupuncture is effective for PNI-induced neurologic deficits, and the potential mechanisms responsible for its effects involve the nervous system remodeling in the process of nerve repair. Moreover, acupuncture promotes neural regeneration and axon sprouting by activating related neurotrophins retrograde transport, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), N-cadherin, and MicroRNAs. Peripheral nerve injury enhances the perceptual response of the central nervous system to pain, causing central sensitization and accelerating neuronal cell apoptosis. Together with this, the remodeling of synaptic transmission function would worsen pain discomfort. Neuroimaging studies have shown remodeling changes in both gray and white matter after peripheral nerve injury. Acupuncture not only reverses the poor remodeling of the nervous system but also stimulates the release of neurotrophic substances such as nerve growth factors in the nervous system to ameliorate pain and promote the regeneration and repair of nerve fibers. In conclusion, the neurological remodeling at the peripheral and central levels in the process of acupuncture treatment accelerates nerve regeneration and repair. These findings provide novel insights enabling the clinical application of acupuncture in the treatment of PNI.
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Affiliation(s)
- Yongke Yang
- Beilun District People’s Hospital, Ningbo, China
| | - Chang Rao
- Tianjin Union Medical Center, Tianjin, China
| | - Tianlong Yin
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shaokang Wang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Huiyan Shi
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Xin Yan
- National Anti-Drug Laboratory Beijing Regional Center, Beijing, China
| | - Lili Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xianggang Meng
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenlong Gu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuzheng Du
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Feng Hong
- Beilun District People’s Hospital, Ningbo, China
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Fractalkine/CX3CR1-Dependent Modulation of Synaptic and Network Plasticity in Health and Disease. Neural Plast 2023; 2023:4637073. [PMID: 36644710 PMCID: PMC9833910 DOI: 10.1155/2023/4637073] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 10/14/2022] [Accepted: 10/18/2022] [Indexed: 01/06/2023] Open
Abstract
CX3CR1 is a G protein-coupled receptor that is expressed exclusively by microglia within the brain parenchyma. The only known physiological CX3CR1 ligand is the chemokine fractalkine (FKN), which is constitutively expressed in neuronal cell membranes and tonically released by them. Through its key role in microglia-neuron communication, the FKN/CX3CR1 axis regulates microglial state, neuronal survival, synaptic plasticity, and a variety of synaptic functions, as well as neuronal excitability via cytokine release modulation, chemotaxis, and phagocytosis. Thus, the absence of CX3CR1 or any failure in the FKN/CX3CR1 axis has been linked to alterations in different brain functions, including changes in synaptic and network plasticity in structures such as the hippocampus, cortex, brainstem, and spinal cord. Since synaptic plasticity is a basic phenomenon in neural circuit integration and adjustment, here, we will review its modulation by the FKN/CX3CR1 axis in diverse brain circuits and its impact on brain function and adaptation in health and disease.
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Yu WL, Kim SN. The effect of acupuncture on pain and swelling of arthritis animal models: A systematic review and meta-analysis. Front Genet 2023; 14:1153980. [PMID: 37113994 PMCID: PMC10126438 DOI: 10.3389/fgene.2023.1153980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 03/27/2023] [Indexed: 04/29/2023] Open
Abstract
Arthritis, the inflammation of joints, attributes to the patient's pain, joint deformation, and limited range of motion. Emerging studies have shown the effects of acupuncture on different types of arthritis. We aimed to assess the effects of acupuncture on arthritis animal models and summarize the related mechanisms. We retrieved studies that met our criteria from PubMed, MEDLINE, EMBASE and the Research Information Service System. The quality assessment was evaluated by using the Systematic Review Centre for Laboratory Animal Experimentation's risk of bias tool. The pain withdrawal latency, pain withdrawal threshold, and paw volume data were digitized using Engauge Digitizer software. The meta-analysis was performed, and the figures were generated using RevMan software. The meta-analysis of data from 21 animal studies revealed that acupuncture increased tolerance to pain stimuli, and reduced swelling in arthritis animals. Although the number of included studies is insufficient, the results suggest acupuncture to be effective in improving arthritis-induced inflammation and pain by regulating the nervous and immune system.
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Luo H, Zhang Y, Zhang J, Shao J, Ren X, Zang W, Cao J, Xu B. Glucocorticoid Receptor Contributes to Electroacupuncture-Induced Analgesia by Inhibiting Nav1.7 Expression in Rats With Inflammatory Pain Induced by Complete Freund's Adjuvant. Neuromodulation 2022; 25:1393-1402. [PMID: 34337820 DOI: 10.1111/ner.13499] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 06/10/2021] [Accepted: 06/29/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND While electroacupuncture (EA) has been used traditionally for the treatment of chronic pain, its analgesic mechanisms have not been fully clarified. We observed in an earlier study that EA could reverse inflammatory pain and suppress high Nav1.7 expression. However, the molecular mechanism underlying Nav1.7 expression regulation is unclear. In this study, we studied the relationship between the glucocorticoid receptor (GR) and Nav1.7 and the role of these molecules in EA analgesia. MATERIALS AND METHODS In this study, we established an inflammatory pain model by intraplantar injection of complete Freund's adjuvant (CFA) in rats. EA stimulation was applied to the ipsilateral "Huantiao" (GB30) and "Zusanli" (ST36) acupoints in the rat model. Western blotting, real-time polymerase chain reaction, immunostaining, intrathecal injection, and chromatin immunoprecipitation (ChIP) assay were performed to determine whether the sodium channel protein Nav1.7 plays a role in CFA-induced pain and whether GR regulates Nav1.7 expression during analgesia following EA stimulation. RESULTS EA application significantly decreased the paw withdrawal threshold thresholds and thermal paw withdrawal latency and suppressed GR and Nav1.7 expression in the dorsal root ganglion. Moreover, treatment with a GR sense oligonucleotide (OND) markedly reversed these alterations. In contrast, treatment with a GR antisense OND along with EA application exerted a better analgesic effect, which was accompanied by the suppression of Nav1.7 and GR protein expression. The ChIP assay showed that the binding activity of GR to the Nav1.7 promoter was enhanced in CFA injected rats and suppressed in EA-treated rats. CONCLUSIONS The present study demonstrated that EA exerted anti-hyperalgesic effects by inhibiting GR expression, which led to Nav1.7 expression modulation in the rat model of CFA-induced inflammatory pain.
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Affiliation(s)
- Huiying Luo
- Department of Anesthesiology, General Hospital of Southern Theatre Command of PLA, Guangzhou, China
| | - Yidan Zhang
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; Neuroscience Research Institute, Zhengzhou University Academy of Medical Sciences, Zhengzhou, China
| | - Jingjing Zhang
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; Neuroscience Research Institute, Zhengzhou University Academy of Medical Sciences, Zhengzhou, China
| | - Jinping Shao
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Xiuhua Ren
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Weidong Zang
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Jing Cao
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; Neuroscience Research Institute, Zhengzhou University Academy of Medical Sciences, Zhengzhou, China.
| | - Bo Xu
- Department of Anesthesiology, General Hospital of Southern Theatre Command of PLA, Guangzhou, China.
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Cui Y, Hu C, Niu C, He M, Qiu X, Yao Q, Tian W, Xu Q. Electroacupuncture attenuates spared nerve injury-induced neuropathic pain possibly by promoting the progression of AMPK/mTOR-mediated autophagy in spinal microglia. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1278. [PMID: 36618785 PMCID: PMC9816825 DOI: 10.21037/atm-22-5273] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 11/24/2022] [Indexed: 12/15/2022]
Abstract
Background Neuropathic pain (NP) is a syndrome that arises from central or peripheral nerve injury, which manifests primarily as hyperalgesia, spontaneous pain, and allodynia. The recent trend has exhibited a shift towards the development of therapies for managing NP. Activation of autophagy is involved in the function of the glial cells, which may be implicated further to attenuate pain. Methods In this study, the analgesic effects of electroacupuncture (EA) were evaluated among NP rats developed using spared nerve injury (SNI). Acupuncture treatment or EA was carried out after 7 days of SNI at two acupoints, i.e., the Zusanli (ST36) and Huantiao (GB30). Results The application of EA was found to attenuate mechanical hyperalgesia. The marker protein for microglial cells (CD11b) alone, without either the astrocyte marker or neuronal marker, was co-expressed with the autophagy indicator p62, as illustrated with immunofluorescence staining. Western blotting demonstrated that the expression levels of p62, Beclin-1, and LC3-II/LC3-I were elevated in the spinal cords of rats in the SNI group compared to the control levels. EA treatment resulted in reduced expression of p62, while the expressions of Beclin-1 and LC3-II/LC3-I were increased. The electron microscopy results indicated that EA could induce autophagy progression in the microglia of the spinal dorsal horn in SNI rats. Furthermore, we explored the causal relationship between EA-induced inhibition of NP and increased autophagic levels in microglia using the AMPK inhibitor compound C, and found that the mechanism of EA-induced analgesia may contribute to the promotion of AMPK/mTOR-mediated autophagy in spinal microglia. Conclusions Our work showed that the analgesic impact of EA is partly related to AMPK/mTOR pathway activation and autophagy induction in microglial cells, providing a potential therapeutic target for NP.
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Affiliation(s)
- Yaomei Cui
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Cheng Hu
- Department of Pain Management, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Cong Niu
- Department of Anesthesiology, The Second affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Menglin He
- The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xizi Qiu
- The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Qiang Yao
- The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Weiqian Tian
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Qian Xu
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
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Xu Q, Niu C, Li J, Hu C, He M, Qiu X, Yao Q, Tian W, Zhang M. Electroacupuncture alleviates neuropathic pain caused by spared nerve injury by promoting AMPK/mTOR-mediated autophagy in dorsal root ganglion macrophage. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1341. [PMID: 36660615 PMCID: PMC9843338 DOI: 10.21037/atm-22-5920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 12/16/2022] [Indexed: 12/28/2022]
Abstract
Background Dorsal root ganglia (DRG) plays an important role in mediating the peripheral sensation transduction through the primary afferent neurons in pain research. Neuropathic pain (NP) is a syndrome of hyperalgesia, spontaneous pain and allodynia caused by central or peripheral nerve injury. Recent trends of study are turning towards the development of therapies for the management of NP. Activation of autophagy in glial cells in the spinal cord has been reported to be associated with attenuation of NP, but the autophagic process in DRG is rarely studied. Methods The analgesic effect of electroacupuncture (EA) was evaluated in NP-induced rats developed using spared nerve injury (SNI). Acupuncture or EA was performed after 7 days of SNI at Zusanli (ST36) and Huantiao (GB30) acupoints. Then, the activation status of autophagy process in DRGs of rats treated with SNI and EA were investigated, and the possible mechanism of the analgesic effect of EA were explored. Results Application of EA has been found to reduce mechanical hyperalgesia. Autophagy indicator p62 was colocalized with the marker proteins for macrophages (CD11b), but not with NeuN (marker protein for neurons) or GFAP (marker protein for satellite glial cells), as shown by immunofluorescence. Western blots results indicate that the expression levels of p62, Beclin-1 and LC3-II in the L4-L6 DRG of rats in the SNI group were increased, compared with that in the control group. EA treatment resulted in decreased expression of p62 and increased expression of Beclin-1 and LC3-II/LC3-I. Furthermore, we explored the causal relationship between EA-induced suppression of NP and increased levels of autophagy in DRG using electron microscopy and the AMPK (AMP-activated protein kinase) inhibitor compound C. Conclusions SNI achieved a significant upregulation of autophagy levels in DRG macrophages. Furthermore, EA attenuated NP, which may contribute to the promotion of AMPK/mTOR (mammalian target of rapamycin)-mediated autophagy in DRG macrophages. Therefore, this strategy provides a new target for therapeutic intervention of NP.
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Affiliation(s)
- Qian Xu
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Cong Niu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, The Second Hospital of Chinese Medicine in Jiangsu Province, Nanjing, China
| | - Jiajing Li
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Cheng Hu
- Department of Pain Management, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Menglin He
- The First Clinical Medical School, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xizi Qiu
- The First Clinical Medical School, Nanjing University of Chinese Medicine, Nanjing, China
| | - Qiang Yao
- The First Clinical Medical School, Nanjing University of Chinese Medicine, Nanjing, China
| | - Weiqian Tian
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Minhao Zhang
- Department of Anesthesiology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China;,Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China
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Farzinpour Z, Liu A, Cao P, Mao Y, Zhang Z, Jin Y. Microglial Engulfment of Spines in the Ventral Zona Incerta Regulates Anxiety-Like Behaviors in a Mouse Model of Acute Pain. Front Cell Neurosci 2022; 16:898346. [PMID: 35910255 PMCID: PMC9337222 DOI: 10.3389/fncel.2022.898346] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 06/17/2022] [Indexed: 12/20/2022] Open
Abstract
Although activation of microglial cells is critical in developing brain disorders, their role in anxiety-like behaviors in pain is still vague. This study indicates that alteration of microglia’s neuronal spine engulfment capacity in ventral zona incerta (ZIV) leads to significant pain and anxiety-like behaviors in mice 1-day post-injection of Complete Freud’s Adjuvant (CFA1D). Performing whole-cell patch-clamp recordings in GABAergic neurons in the ZIV (ZIVGABA) in brain slices, we observed decreased activity in ZIvGABA and reduced frequency of the miniature excitatory postsynaptic currents (mEPSCs) in ZIVGABA of CFA1D mice compared with the saline1D mice. Besides, chemogenetic activation of ZIVGABA significantly relieved pain and anxiety-like behaviors in CFA1D mice. Conversely, in naïve mice, chemogenetic inhibition of ZIVGABA induced pain and anxiety-like behaviors. Interestingly, we found changes in the density and morphology of ZIVMicroglia and increased microglial engulfment of spines in ZIV of CFA1D mice. Furthermore, pain sensitization and anxiety-like behaviors were reversed when the ZIVMicroglia of CFA1D-treated mice were chemically inhibited by intra-ZIV minocycline injection, accompanied by the recovery of decreased ZIVGABA excitability. Conclusively, our results provide novel insights that dysregulation of microglial engulfment capacity encodes maladaptation of ZIVGABA, thus promoting the development of anxiety-like behaviors in acute pain.
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Affiliation(s)
- Zahra Farzinpour
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - An Liu
- Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Peng Cao
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yu Mao
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Zhi Zhang
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- *Correspondence: Zhi Zhang,
| | - Yan Jin
- Stroke Center and Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Yan Jin,
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Gao W, Shen L, Long DD, Pan TT, Wang D, Chai XQ, Hu SS. Angiotensin II type 2 receptor pharmacological agonist, C21, reduces the inflammation and pain hypersensitivity in mice with joint inflammatory pain. Int Immunopharmacol 2022; 110:108921. [PMID: 35724606 DOI: 10.1016/j.intimp.2022.108921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/19/2022] [Accepted: 06/01/2022] [Indexed: 11/15/2022]
Abstract
Primary and secondary hyperalgesia develop in response to chronic joint inflammation due to peripheral and central mechanisms. Synovial macrophage and spinal microglia are involved in pain sensitization in arthritis. The level of angiotensin II type 2 receptor (AT2R) is related to the severity of arthritis. This study aimed to determine the role of AT2R in primary and secondary hyperalgesia in joint inflammatory pain in mice. After intra-articular CFA injection, primary hyperalgesia in the ipsilateral knee joint was measured by pressure application meter and gait analysis, secondary hypersensitivity in ipsilateral hind-paw was measured by von-Frey and Hargreaves tests following a combination of global AT2R-deficient (Agtr2-/-) mice and AT2R pharmacological agonist C21. Synovial macrophage and spinal microglia were collected for flow cytometry. Morphological reconstruction of microglia was detected by immunostaining. AT2R expression was investigated by quantitative polymerase chain reaction and western blot. Neuronal hyperactivity was evaluated by c-Fos and CGRP immunostaining. We found that pain hypersensitivity and synovial inflammation in Agtr2-/- mice were significantly exacerbated compared with wild-type mice; conversely, systemically administrated C21 attenuated both of the symptoms. Additionally, spinal microglia were activated, and an abundant increase of spinal AT2R was expressed on activated microglia in response to peripheral joint inflammation. Intrathecally-administrated C21 reversed the secondary hypersensitivity, accompanied by alleviation of spinal microglial activation, spinal neuronal hyperactivity, and calcitonin gene-related peptide content. These findings revealed a beneficial role of AT2R activating stimulation against pain hypersensitivity in joint inflammatory pain via direct modulation of synovial macrophage and spinal microglial activity.
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Affiliation(s)
- Wei Gao
- Anhui Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Liang Shen
- Department of Anesthesiology, Anhui Provincial Hospital Affiliated to Medical University, Hefei 230036, China
| | - Dan-Dan Long
- Department of Anesthesiology, Anhui Provincial Hospital Affiliated to Medical University, Hefei 230036, China
| | - Ting-Ting Pan
- Department of Anesthesiology, Anhui Provincial Hospital Affiliated to Medical University, Hefei 230036, China
| | - Di Wang
- Department of Anesthesiology, Anhui Provincial Hospital Affiliated to Medical University, Hefei 230036, China
| | - Xiao-Qing Chai
- Anhui Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
| | - Shan-Shan Hu
- Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
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Chen Y, Zhou Y, Li XC, Ma X, Mi WL, Chu YX, Wang YQ, Mao-Ying QL. Neuronal GRK2 regulates microglial activation and contributes to electroacupuncture analgesia on inflammatory pain in mice. Biol Res 2022; 55:5. [PMID: 35115050 PMCID: PMC8812183 DOI: 10.1186/s40659-022-00374-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 01/22/2022] [Indexed: 12/30/2022] Open
Abstract
Background G protein coupled receptor kinase 2 (GRK2) has been demonstrated to play a crucial role in the development of chronic pain. Acupuncture is an alternative therapy widely used for pain management. In this study, we investigated the role of spinal neuronal GRK2 in electroacupuncture (EA) analgesia. Methods The mice model of inflammatory pain was built by subcutaneous injection of Complete Freund’s Adjuvant (CFA) into the plantar surface of the hind paws. The mechanical allodynia of mice was examined by von Frey test. The mice were subjected to EA treatment (BL60 and ST36 acupuncture points) for 1 week. Overexpression and downregulation of spinal neuronal GRK2 were achieved by intraspinal injection of adeno associated virus (AAV) containing neuron-specific promoters, and microglial activation and neuroinflammation were evaluated by real-time PCR. Results Intraplantar injection with CFA in mice induced the decrease of GRK2 and microglial activation along with neuroinflammation in spinal cord. EA treatment increased the spinal GRK2, reduced neuroinflammation, and significantly decreased CFA-induced mechanical allodynia. The effects of EA were markedly weakened by non-cell-specific downregulation of spinal GRK2. Further, intraspinal injection of AAV containing neuron-specific promoters specifically downregulated neuronal GRK2, and weakened the regulatory effect of EA on CFA-induced mechanical allodynia and microglial activation. Meanwhile, overexpression of spinal neuronal GRK2 decreased mechanical allodynia. All these indicated that the neuronal GRK2 mediated microglial activation and neuroinflammation, and subsequently contributed to CFA-induced inflammatory pain. Conclusion The restoration of the spinal GRK2 and subsequent suppression of microglial activation and neuroinflammation might be an important mechanism for EA analgesia. Our findings further suggested that the spinal GRK2, especially neuronal GRK2, might be the potential target for EA analgesia and pain management, and we provided a new experimental basis for the EA treatment of pain. Supplementary Information The online version contains supplementary material available at 10.1186/s40659-022-00374-6.
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Affiliation(s)
- Yu Chen
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Integrative Medicine, Fudan University, Shanghai, 200032, People's Republic of China
| | - Yang Zhou
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, People's Republic of China
| | - Xiao-Chen Li
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Integrative Medicine, Fudan University, Shanghai, 200032, People's Republic of China
| | - Xue Ma
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Integrative Medicine, Fudan University, Shanghai, 200032, People's Republic of China
| | - Wen-Li Mi
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Integrative Medicine, Fudan University, Shanghai, 200032, People's Republic of China
| | - Yu-Xia Chu
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Integrative Medicine, Fudan University, Shanghai, 200032, People's Republic of China
| | - Yan-Qing Wang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Integrative Medicine, Fudan University, Shanghai, 200032, People's Republic of China.,State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, People's Republic of China.,Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, 200433, People's Republic of China
| | - Qi-Liang Mao-Ying
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Integrative Medicine, Fudan University, Shanghai, 200032, People's Republic of China. .,Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, 200433, People's Republic of China.
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Chun S, Lee JH, Yoon SY, Kwon YB. The Peripheral Role of CCL2 in the Anti-Nociceptive Effect of Sigma-1 Receptor Antagonist BD1047 on Inflammatory Hyperalgesia in Rats. Int J Mol Sci 2021; 22:11730. [PMID: 34769165 PMCID: PMC8583891 DOI: 10.3390/ijms222111730] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/25/2021] [Accepted: 10/28/2021] [Indexed: 12/02/2022] Open
Abstract
Our recent study demonstrated that the CC-chemokine ligand 2 (CCL2) present in primary afferent fibers (PAFs) plays an important role in the microglia-dependent neuronal activation associated with zymosan-induced inflammatory pain. The present study was aimed to evaluate whether BD1047 (a prototypical sigma-1 receptor (Sig-1R) antagonist) is capable of modifying elevated levels of inflammation-evoked CCL2 as a peripheral antinociceptive mechanism. In DRG primary culture, zymosan dose-dependently increased CCL2 release from isolectin B4 (IB4)-positive DRG neurons, a process that was inhibited by co-culture with BD1047. Single treatment of BD1047 before intraplantar injection of zymosan in rats significantly reduced thermal hyperalgesia and mechanical hyperalgesia, as well as CCL2 expression in DRG neurons and microglia activation in the spinal dorsal horn. In the Complete Freund's adjuvant (CFA)-induced inflammation model, repeated administration of BD1047 dramatically attenuated thermal hyperalgesia and mechanical hyperalgesia, and significantly diminished CCL2 immunoreactivity and microglia activation. Notably, CFA-induced inflammation significantly increased Sig-1R immunoreactivity in DRG neurons, which was co-localized with CCL2 and IB4, respectively. Taken together, our results suggest that BD1047's anti-nociceptive property was substantially mediated by the inhibition of CCL2 release in unmyelinated PAFs and that this may, in turn, have attenuated the spinal microglia activation that is associated with inflammatory pain.
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Affiliation(s)
- Sungkun Chun
- Department of Physiology, Institute for Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Korea;
| | - Jun-Ho Lee
- Department of Anesthesiology and Pain Medicine, Jeonbuk National University Medical School and Hospital, Jeonju 54907, Korea;
| | - Seo-Yeon Yoon
- Department of Pet Animal, Division of Health and Life Science, Daejeon Institute of Science and Technology, Daejeon 35408, Korea;
| | - Young-Bae Kwon
- Department of Pharmacology, Institute for Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Korea
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King H, Forrester M. Electroacupuncture For Alleviation Of Phantom Limb Pain. JOURNAL OF REHABILITATION MEDICINE - CLINICAL COMMUNICATIONS 2021; 4:1000063. [PMID: 34276906 PMCID: PMC8278009 DOI: 10.2340/20030711-1000063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 05/10/2021] [Indexed: 11/21/2022]
Abstract
Phantom limb pain is clinically defined as the perception of pain or discomfort in a limb that no longer exists. Most amputees will experience phantom limb pain, which is associated with a low health-related quality of life. Phantom limb pain represents an important challenge in finding an effective therapy. The scientific evidence for best practice is weak, and is characterized by various clinical reports describing the pragmatic use of drugs and interventional techniques. Recent approaches to restore the sensory motor input have shown promise. One such technique is electroacupuncture. We report here a case study of a male in his 30s who sustained severe injuries, including a high transfemoral amputation, as a result of being hit by a car. An electroacupuncture treatment protocol was used. Over the course of 3 months, electroacupuncture alleviated the patient’s phantom limb pain, minimized his use of drugs, and improved his sleep and quality of life. The effect of electroacupuncture treatment lasted for 3–4 months, and successful top-up treatment maintained his pain relief. The results are in line with a study comparing massage and electroacupuncture in patients with spinal cord injury with neurogenic pain; a limited number of patients treated with electroacupuncture were significantly alleviated of their pain for months. This case report suggests that electroacupuncture may be useful in patients with phantom limb pain.
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