Scientific Reports
·
2021
·Vol. 11
·期 1
·1-9
·
IF 4.38
Zhou Zhiyong,Qiu Nanqing,Ou Yuntao,Wei Qianqian,Tang Wenting,Zheng Mingcong,Xing Yaluan,Li Jie-Jia,Ling Yong,Li Junxu,Zhu Qing
Chronic pain is a significant public health problem that afflicts nearly 30% of the global population, but current pharmacotherapies are insufficient. Previous report indicated that N -demethylsinomenine, an active metabolite of sinomenine, is efficacious against postoperative pain. The present study investigated whether N -demethylsinomenine is effective for chronic painful conditions or whether repeated treatment alters its effect. Both chronic constriction injury (CCI) surgery and complete Freund’s adjuvant (CFA) intraplantar injection induced significant and reliable mechanical allodynia at least for 7 days. Acute treatment with N -demethylsinomenine (10–40 mg/kg, i.p.) dose-dependently attenuated the mechanical allodynia both in CCI-induced neuropathic pain and CFA-induced inflammatory pain in mice. The potency of N -demethylsinomenine for reducing CFA-induced mechanical allodynia was slightly higher than sinomenine. During the period of repeated treatment, N -demethylsinomenine maintained its anti-allodynic effect against both neuropathic and inflammatory pain without producing carry-over effect. Pretreatment with bicuculline, a selective γ-aminobutyric acid type A (GABA A ) receptor antagonist, almost completely blocked the anti-allodynia of N -demethylsinomenine (40 mg/kg) both in CCI and CFA-treated mice. Our findings indicated that N -demethylsinomenine exhibits GABA A receptor-mediated anti-allodynic effects in mouse models of neuropathic and inflammatory pain, suggesting it may be a useful novel pharmacotherapy for the control of chronic pain.
研究领域:
药理学
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疼痛研究
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神经科学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2021
·
IF 4.932
Yonglan Ruan,Jinying Ling,Fan Ye,Nuo Cheng,Fei Wu,Zongxiang Tang,Xiaolan Cheng,Hongquan Liu
Background Treatment of chronic inflammatory pain remains a major goal in the clinic. It is thus of prime importance to characterize inherent pathophysiological pathways to design new therapeutic strategies and analgesics for pain management. Paeoniflorin (PF), a monoterpenoid glycoside from Paeonia lactiflora Pallas plants, possesses promising anti-nociceptive property. However, therapeutic effect and underlying mechanism of action of PF on inflammatory pain have not yet been fully elucidated. In this study, we aim to investigate the analgesic effect further and clarify its mechanism of action of PF on complete freund’s adjuvant (CFA)-evoked inflammatory pain. Methods Twenty-four male mice were divided into 3 groups: sham, CFA, and CFA + PF groups (n = 8/group). Mice were treated with normal saline or PF (30 mg/kg) for 11 days. Footpad swelling (n = 8/group), mechanical (n = 8/group) and thermal hypersensitivity (n = 8/group) were measured to evaluate the analgesic effect of PF on CFA-injected mice. At the end of the animal experiment, blood and L4-L6 dorsal root ganglion neurons were collected to assess the therapeutic effect of PF on CFA-induced inflammatory pain. Next, hematoxylin and eosin, quantitative realtime PCR, ELISA, capsaicin and dimethyl succinate induced pain test (n = 8/group), motor coordination test (n = 8/group), tail flicking test (n = 8/group), pyruvate and succinate dehydrogenase assay (n = 6/group), immunohistochemical staining, were performed to clarify the action mechanism of PF on CFA-evoked inflammatory pain. Besides, the effect of PF on TRPV1 was evaluated by whole-cell patch clamp recording on primary neurons (n = 7). Finally, molecular docking further performed to evaluate the binding ability of PF to TRPV1. Results PF significantly relieved inflammatory pain ( P < 0.001 ) and paw edema ( P < 0.001 ) on a complete Freund adjuvant (CFA)-induced peripheral inflammatory pain model. Furthermore, PF inhibited neutrophil infiltration ( P < 0.01 ), IL-1β increase ( P < 0.01 ), and pain-related peptide substance P release ( P < 0.001 ). Intriguingly, CFA-induced succinate aggregation was notably reversed by PF via modulating pyruvate and SDH activity ( P < 0.01 ). In addition, PF dampened the high expression of subsequent succinate receptor SUCNR1 ( P < 0.01 ), HIF-1α ( P < 0.05 ), as well as the activation of NLPR3 inflammasome ( P < 0.05 ) and TRPV1 ( P < 0.05 ). More importantly, both capsaicin and dimethyl succinate supplementation obviously counteracted the pain-relieving effect of PF and TRPV1 ( P < 0.01 or P < 0.001 ). Conclusion Our findings suggest that PF can significantly relieve CFA-induced paw swelling, as well as mechanical and thermal hyperalgesia. PF alleviated inflammatory pain partly through inhibiting the activation of TRPV1 and succinate/SUCNR1-HIF-1α/NLPR3 pathway. Furthermore, we found that PF exerted its analgesic effect without affecting motor coordination and pain-related cold ion-channels. In summary, this study may provide valuable evidence for the potential application of PF as therapeutic strategy for inflammatory pain treatment.
研究领域:
药理学
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疼痛管理
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神经科学
·
炎症
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CNS Neuroscience & Therapeutics
·
2025
·Vol. 31
·期 1
·e70197
·
IF 5
Weiwei Rong,Xunjia Qian,Yujian Yin,Yipeng Gu,Weiyi Su,Jie‐Jia Li,Yue Xu,Hongyan Zhu,Junxu Li,Qing Zhu
NDSM demonstrates good analgesic efficacy in preclinical pain models with fewer side effects than sinomenine. The analgesic effects of NDSM are mediated primarily by GABRA2 and partially by GABRA3. NDSM shows promise as a novel analgesic candidate for chronic pain management.
研究领域:
药理学
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疼痛研究
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PAIN
·
2023
·
IF 4
Yuehong Zhang,Xuelin Huang,Wen-Jun Xin,Shilang He,Jie Deng,Xiangcai Ruan
Projections from the periaqueductal gray (PAG) to the rostral ventromedial medulla (RVM) are known to engage in descending pain modulation, but how the neural substrates of the PAG-RVM projections contribute to neuropathic pain remains largely unknown. In this study, we showed somatostatin-expressing glutamatergic neurons in the lateral/ventrolateral PAG that facilitate mechanical and thermal hypersensitivity in a mouse model of chemotherapy-induced neuropathic pain. We found that these neurons form direct excitatory connections with neurons in the RVM region. Inhibition of this PAG-RVM projection alleviates mechanical and thermal hypersensitivity associated with neuropathy, whereas its activation enhances hypersensitivity in the mice. Thus, our findings revealed that somatostatin neurons within the PAG-RVM axial are crucial for descending pain facilitation and can potentially be exploited as a useful therapeutic target for neuropathic pain. Perspective We report the profound contribution of somatostatin neurons within the PAG-RVM projections to descending pain facilitation underlying neuropathic pain. These results may help to develop central therapeutic strategies for neuropathic pain.
研究领域:
神经科学
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疼痛研究
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Kaichao Song,Yumei Hao,Xiaochuan Tan,Hongdong Huang,Lulu Wang,Wensheng Zheng
Ziconotide (ZIC) is an N-type calcium channel antagonist for treating severe chronic pain that is intolerable, or responds poorly to the administration of other drugs, such as intrathecal morphine and systemic analgesics. As it can only work in the brain and cerebrospinal fluid , intrathecal injection is the only administration route for ZIC. In this study, borneol (BOR)-modified liposomes (LIPs) were fused with exosomes from mesenchymal stem cells (MSCs) and loaded with ZIC to prepare microneedles (MNs) to improve the efficiency of ZIC across the blood-brain barrier. To evaluate local analgesic effects of MNs, the sensitivity of behavioral pain to thermal and mechanical stimuli was tested in animal models of peripheral nerve injury , diabetes-induced neuropathy pain, chemotherapy-induced pain, and ultraviolet-B (UV-B) radiation-induced neurogenic inflammatory pain . BOR-modified LIPs loaded with ZIC were spherical or nearly spherical, with a particle size of about 95 nm and a Zeta potential of −7.8 mV. After fusion with MSC exosomes, the particle sizes of LIPs increased to 175 nm, and their Zeta potential increased to −3.8 mV. The nano-MNs constructed based on BOR-modified LIPs had good mechanical properties and could effectively penetrate the skin to release drugs. The results of analgesic experiments showed that ZIC had a significant analgesic effect in different pain models. In conclusion, the BOR-modified LIP membrane-fused exosome MNs constructed in this study for delivering ZIC provide a safe and effective administration for chronic pain treatment, as well as great potential for clinical application of ZIC.
研究领域:
药学
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纳米技术
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神经科学
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疼痛管理
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Neural Regeneration Research
·
2024
·Vol. 19
·期 12
·2708
·
IF 5.9
Fang He,Li Mengjie,Yang Jingchen,Ma Shunping,Zhang Li,Yang Hongqi,Tang Qiongyan,Cao Jing,Yang Weimin
Thalamic hemorrhage can lead to the development of central post-stroke pain. Changes in histone acetylation levels, which are regulated by histone deacetylases, affect the excitability of neurons surrounding the hemorrhagic area. However, the regulatory mechanism of histone deacetylases in central post-stroke pain remains unclear. Here, we show that iron overload leads to an increase in histone deacetylase 2 expression in damaged ventral posterolateral nucleus neurons. Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium (Kv) channel subunit gene in a rat model of central post-stroke pain, thereby increasing Kcna2 expression and relieving central pain. However, in the absence of nerve injury, increasing histone deacetylase 2 expression decreased Kcna2 expression, decreased Kv current, increased the excitability of neurons in the ventral posterolateral nucleus area, and led to neuropathic pain symptoms. Moreover, treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage, reversed histone deacetylase 2 upregulation and Kv1.2 downregulation, and alleviated mechanical hypersensitivity in central post-stroke pain rats. These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation, mediated by iron overload, are important factors in central post-stroke pain pathogenesis and could serve as new targets for central post-stroke pain treatment.
研究领域:
神经科学
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药理学
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分子生物学
·
神经病学
✓ 已验证
DOI
PubMed
高影响因子
PLOS BIOLOGY
·
2024
·Vol. 22
·期 2
·e3002518
·
IF 7.8
Ying-Di Wang,Shu-Ting Bao,Yuan Gao,Jin Chen,Tao Jia,Cui Yin,Jun-Li Cao,Cheng Xiao,Chunyi Zhou
Neurons in the subthalamic nucleus (STN) become hyperactive following nerve injury and promote pain-related responses in mice. Considering that the anterior cingulate cortex (ACC) is involved in pain and emotion processing and projects to the STN, we hypothesize that ACC neurons may contribute to hyperactivity in STN neurons in chronic pain. In the present study, we showed that ACC neurons enhanced activity in response to noxious stimuli and to alterations in emotional states and became hyperactive in chronic pain state established by spared nerve injury of the sciatic nerve (SNI) in mice. In naïve mice, STN neurons were activated by noxious stimuli, but not by alterations in emotional states. Pain responses in STN neurons were attenuated in both naïve and SNI mice when ACC neurons were inhibited. Furthermore, optogenetic activation of the ACC-STN pathway induced bilateral hyperalgesia and depression-like behaviors in naive mice; conversely, inhibition of this pathway is sufficient to attenuate hyperalgesia and depression-like behaviors in SNI mice and naïve mice subjected to stimulation of STN neurons. Finally, mitigation of pain-like and depression-like behaviors in SNI mice by inhibition of the ACC-STN projection was eliminated by activation of STN neurons. Our results demonstrate that hyperactivity in the ACC-STN pathway may be an important pathophysiology in comorbid chronic pain and depression. Thus, the ACC-STN pathway may be an intervention target for the treatment of the comorbid chronic pain and depression.
研究领域:
神经科学
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疼痛研究
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抑郁症
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神经通路
✓ 已验证
DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
·
2025
·
IF 4.6
Wen-Hui Ni,Ke Wang,Yun Wang,Jia Lu,Chun-Ting Lu,Wen Rong,Yi-Feng Gu,Wen-Juan Qian,Hai-Long Zhang
Chronic inflammatory pain is a top priority for arthritis patients seeking medical care. Despite the availability of NSAIDs and glucocorticoids, pain management becomes increasingly challenging due to central and peripheral sensitization. Previous studies have shown that Matrix metalloproteinase 2 (MMP2) promotes neuroinflammation by cleaving extracellular matrix proteins and activating pro-inflammatory cytokines. Folic acid acts as a promising candidate for the treatment of neuroinflammatory diseases due to its neuroprotective effects. However, the role of folic acid in inflammatory pain remains unclear. This study investigated the analgesic mechanisms of folic acid in inflammatory pain. Adult rats underwent inflammatory pain by injecting complete freund's adjuvant (CFA) into the right hindpaw. Behavioral tests were used to assess the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). The results demonstrated that CFA injection induced abnormal mechanical and thermal pain and increased MMP2 expression in L3-L5 DRG and SDH of CFA rats. MMP2 was mainly expressed in neurons rather than glial cells in L3-L5 DRG of CFA rats. We further discovered that MMP2 inhibitor auraptene or knockdown alleviated inflammatory pain in CFA rats. Interestingly, we observed that long-term folic acid treatment reversed MMP2 overexpression, resulting in sustained relief of chronic inflammatory pain. Consistently, long-term folic acid treatment also relieved pain-induced anxiety. These results indicated that folic acid had a protective role in chronic inflammatory pain and pain-induced anxiety by repressing MMP2 expression. Folic acid or auraptene might be promising therapeutic options for the treatment of chronic inflammatory pain.
研究领域:
药理学
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神经科学
·
炎症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH
·
2023
·
IF 2.9
Yong-Juan Gu,He-Ya Qian,Fang Zhou,Ling Zhang,Long Chen,Yu Song,Ya-Nan Chen,Hai-Long Zhang
Background Bone cancer pain (BCP) remains a clinical challenge due to the limited and side effects of therapeutic methods. Folic acid has been known as an FDA approved dietary supplement and proved to have an analgesic effect in neuropathic pain. Here we investigate the role and mechanism of folic acid in bone cancer pain of a rat model. Methods Walker 256 tumor cells were inoculated into the left tibia of rats to induce bone cancer pain model. Pain reflex were assessed by paw withdrawal threshold (PWT) response to Von Frey filaments and paw withdrawal latency (PWL) response to thermal stimulation. Folic acid was injected intraperitoneally to evaluate its analgesic effect in rats with bone cancer pain. Western blotting and qPCR were used to determine P2X2/3 receptor protein and mRNA levels in ipsilateral L4-6 dorsal root ganglion (DRG) and spinal dorsal horn (SDH). Results The PWT and PWL of rats with bone cancer pain were obviously decreased compared to the naïve and sham rats. Interestingly, continuous folic acid treatment significantly increased the PWT and PWL of rats with bone cancer pain. P2X2 and P2X3 receptors were clearly upregulated at both mRNA and protein expression in L4-6 DRG and SDH of rats with bone cancer pain. P2X2 and P2X3 receptors were mainly localized with CGRP (calcitonin gene-related peptide) or IB4 (isolectin B4) positive neurons in L4-6 DRG of rats with bone cancer pain. Notably, continuous folic acid treatment significantly reduced the expression of P2X2 and P2X3 receptors in L4-6 DRG and SDH of rats with bone cancer pain. Finally, intrathecal injection of A317491 (a selective antagonist of P2X2/3 receptors) markedly elevated the PWT and PWL of rats with bone cancer pain. Conclusion These results suggest that folic acid has an effective antinociceptive effect on bone cancer pain, which is mediated by downregulating P2X2/3 receptors in L4-6 DRG and SDH of rats with bone cancer pain. Folic acid may be a novel therapeutic strategy in cancer patients for pain relief.
研究领域:
药理学
·
肿瘤学
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2016
·Vol. 6
·期 1
·1-10
·
IF 5.228
Zhu Qing,Mao Li-Na,Liu Cheng-Peng,Sun Yue-Hua,Jiang Bo,Zhang Wei,Li Jun-Xu
Vitexin, a C-glycosylated flavone present in several medicinal herbs, has showed various pharmacological activities including antinociception. The present study investigated the antinociceptive effects of vitexin in a mouse model of postoperative pain. This model was prepared by making a surgical incision on the right hindpaw and von Frey filament test was used to assess mechanical hyperalgesia. Isobolographical analysis method was used to examine the interaction between vitexin and acetaminophen. A reliable mechanical hyperalgesia was observed at 2 h post-surgery and lasted for 4 days. Acute vitexin administration (3–10 mg/kg, i.p.) dose-dependently relieved this hyperalgesia, which was also observed from 1 to 3 days post-surgery during repeated daily treatment. However, repeated vitexin administration prior to surgery had no preventive value. The 10 mg/kg vitexin-induced antinociception was blocked by the opioid receptor antagonist naltrexone or the GABA A receptor antagonist bicuculline. The doses of vitexin used did not significantly suppress the locomotor activity. In addition, the combination of vitexin and acetaminophen produced an infra-additive effect in postoperative pain. Together, though vitexin-acetaminophen combination may not be useful for treating postoperative pain, vitexin exerts behaviorally-specific antinociception against postoperative pain mediated through opioid receptors and GABA A receptors, suggesting that vitexin may be useful for the control of postoperative pain.
研究领域:
药理学
·
疼痛研究
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神经科学
✓ 已验证
DOI
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2021
·
IF 7.328
Yongmei Ge,Kui Wang,Huili Li,Ye Tian,Yutong Wu,Zhaowei Lin,Yangyang Lin,Yansong Wang,Jiarong Zhang,Bin Tang
Bone pain is the primary problem for patients with osteoporosis. Ketoprofen is clinically used to treat osteoporotic pain, while long-term oral administration of ketoprofen can cause some side effects. In addition, osteoporosis is also accompanied by bone mass loss and inflammation. In this study, we designed a multifunctional drug (Ket@Mg-MOF-74) adopted Mg-MOF-74 to load ketoprofen to treat osteoporotic pain, bone loss and inflammation comprehensively. Mg-MOF-74 was prepared, and the physicochemical characterization proved that it had excellent physical and chemical stability. Ket@Mg-MOF-74 was synthesized by post-synthetic modification method and a high loading rate of ketoprofen was confirmed. Drug release and ion release experiments indicated Ket@Mg-MOF-74 had a good controlled release of ketoprofen and Mg in solution. Cell experiments in vitro proved the compound drug could significantly reduce the expression of pain-related genes of cyclooxygenase 2 (COX2), obviously up-regulated the expression of osteogenic cytokines and remarkably down-regulated the secretion of pro-inflammatory factors. Therefore, Ket@Mg-MOF-74 is believed a promising painkiller for osteoporotic bone pain, with the function of anti-inflammatory and promoting bone formation.
研究领域:
药理学
·
材料科学
·
骨生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Xin Tan,Yi Zhou,Yaxin Qin,Linjie Wu,Ruizhi Yang,Xiaoyan Bao,Ruolin Jiang,Xiaoyan Sun,Xufang Ying,Zhiqing Ben,Qi Dai,Zhicheng Zhang,Kai Zeng,Min Han
Regional analgesia based on the local anesthetic ropivacaine plays a crucial role in postoperative pain management and recovery; however, the short duration of analgesia limits its clinical potential. Various drug delivery systems such as microparticles and lipid carriers have been used to prolong the analgesic effect, yet most of them are prone to abrupt release from the site of administration or have poor analgesic effects of less than 48 h, which fail to meet the needs of postoperative analgesia. In this study, a low-molecular-weight gelator sodium deoxycholate-based hydrogel loaded with ropivacaine (DC-ROP gel) was designed for long-acting analgesia. The noncovalent interaction between ropivacaine and sodium deoxycholate helps to improve the stability and sustained release performance of the gel. This internal drug-binding hydrogel also avoids experiencing the burst release effect commonly seen in polymer hydrogels previously reported for the slow release of local anesthetics. DC-ROP gel exhibited the dual advantages of self-healing after compression and long-term controlled release. In mice with inflammatory pain, DC-ROP gel achieved peripheral nerve block for more than 1 week after a single injection. Histological and blood biochemical analyses confirmed that the DC-ROP gel did not produce systemic toxicity, and cytotoxicity experiments demonstrated that the DC-ROP gel resulted in low irritation. These results suggest that DC-ROP gel provides a promising strategy for local anesthetics in long-term postoperative pain management, broadening the potential of bile salt-based low-molecular-weight hydrogels for drug delivery.
研究领域:
药剂学
·
药物递送系统
·
疼痛管理
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）