In a recent work published in Neuron,Xu et al.identified a novel contribution of G protein-coupled receptor 37-like 1(GPR37L1),which is identified to be expressed by spinal astrocytes,to the regulation of neuropathic ...In a recent work published in Neuron,Xu et al.identified a novel contribution of G protein-coupled receptor 37-like 1(GPR37L1),which is identified to be expressed by spinal astrocytes,to the regulation of neuropathic pain[1].By interacting and enhancing the activity of glutamate transporter-1(GLT-1)in spinal astrocytes,GPR37L1 promotes glutamate uptake by spinal astrocytes and reduces excitatory synaptic transmission in the spinal dorsal horn,all of which contribute to the resolution of chronic neuropathic pain.展开更多
Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein ...Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this effect.In this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic analysis.The results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer pain.In addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain hypersensitivity.Furthermore,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression.Moreover,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was enhanced.Mechanistically,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F.Additionally,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 methylation.These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.展开更多
Objective:Neuropathic pain(NP)is one of the most common forms of chronic pain,yet current treatment options are limited in effectiveness.Peripheral nerve injury activates spinal microglia,altering their inflammatory r...Objective:Neuropathic pain(NP)is one of the most common forms of chronic pain,yet current treatment options are limited in effectiveness.Peripheral nerve injury activates spinal microglia,altering their inflammatory response and phagocytic functions,which contributes to the progression of NP.Most current research on NP focuses on microglial inflammation,with relatively little attention to their phagocytic function.Early growth response factor 2(EGR2)has been shown to regulate microglial phagocytosis,but its specific role in NP remains unclear.This study aims to investigate how EGR2 modulates microglial phagocytosis and its involvement in NP,with the goal of identifying potential therapeutic targets.Methods:Adult male Sprague-Dawley(SD)rats were used to establish a chronic constriction injury(CCI)model of the sciatic nerve.Pain behaviors were assessed on days 1,3,7,10,and 14 post-surgery to confirm successful model induction.The temporal and spatial expression of EGR2 in the spinal cord was examined using real-time quantitative PCR(RT-qPCR),Western blotting,and immunofluorescence staining.Adeno-associated virus(AAV)was used to overexpress EGR2 in the spinal cord,and behavioral assessments were performed to evaluate the effects of EGR2 modulation of NP.CCI and lipopolysaccharide(LPS)models were established in animals and microglial cell lines,respectively,and changes in phagocytic activity were measured using RT-qPCR and fluorescent latex bead uptake assays.After confirming the involvement of microglial phagocytosis in NP,AAV was used to overexpress EGR2 in both in vivo and in vitro models,and phagocytic activity was further evaluated.Finally,eukaryotic transcriptome sequencing was conducted to screen differentially expressed mRNAs,followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses to identify potential downstream effectors of EGR2.Results:The CCI model successfully induced NP.Following CCI,EGR2 expression in the spinal cord was upregulated in parallel with NP development.Overexpression of EGR2 via spinal AAV injection enhanced microglial phagocytic activity and increased pain hypersensitivity in rats.Both animal and cellular models showed that CCI or LPS stimulation enhanced microglial phagocytosis,which was further amplified by EGR2 overexpression.Transcriptomic analysis of spinal cord tissues from CCI rats overexpressing EGR2 revealed upregulation of numerous genes associated with microglial phagocytosis and pain regulation.Among them,Lag3 emerged as a potential downstream target of EGR2.Conclusion:EGR2 contributes to the maintenance of NP by enhancing microglial phagocytosis in the spinal dorsal horn.展开更多
Objective To explore the therapeutic effect of LuoFuShan Rheumatism Plaster(LFS)on neuropathic pain(NP)and its molecular mechanism.Methods Mouse models of sciatic nerve chronic constriction injury(CCI)were treated wit...Objective To explore the therapeutic effect of LuoFuShan Rheumatism Plaster(LFS)on neuropathic pain(NP)and its molecular mechanism.Methods Mouse models of sciatic nerve chronic constriction injury(CCI)were treated with low,medium,and high doses(2.2,4.4,and 8.8 cm2,respectively)of LFS by topical application for 14 consecutive days.The therapeutic effects were assessed by evaluating the mechanical withdrawal threshold(MWT),paw withdrawal latency(PWL),plasma IL-6 and TNF-αlevels,and histopathology of the sciatic nerve.Network pharmacology and molecular docking were used to identify the key targets and signaling pathways.The key targets were verified by RT-qPCR and immunohistochemistry.The biosafety of LFS was evaluated by measuring the organ indices and damage indicators of the heart,liver,and kidneys.Results Compared with the CCI group,LFS dose-dependently increased MWT and PWL,reduced plasma IL-6 and TNF-αlevels,and alleviated sciatic nerve inflammation in the mouse models.Network pharmacology identified 378 bioactive compounds targeting 279 NPassociated genes enriched in TLR and TNF signaling.Molecular docking showed that quercetin and ursolic acid in LFS could stably bind to TLR4 and TNF-α.In the mouse models of sciatic nerve CCI,LFS significantly downregulated the mRNA expression levels of Tlr4 and Tnf-αin the spinal cord in a dose-dependent manner and lowered the protein expressions of TLR4 and TNF-αin the sciatic nerve.LFS treatment did not cause significant changes in the organ indices or damage indicators of the heart,liver and kidneys as compared with those in the CCI model group and sham-operated group.Conclusion LFS alleviates NP in mice by suppression of TLR4/TNF-α-mediated neuroinflammation with a good safety profile.展开更多
Objective To determine the prevalence,distribution,and associated clinical factors of chronic neuropathic cancer pain(CNCP)among outpatients with chronic cancer pain(CCP)and to inform improved recognition and manageme...Objective To determine the prevalence,distribution,and associated clinical factors of chronic neuropathic cancer pain(CNCP)among outpatients with chronic cancer pain(CCP)and to inform improved recognition and management.Methods In this cross-sectional study,consecutive outpatients with CCP diagnosed according to the International Association for the Study of Pain(IASP)criteria were recruited from the pain clinic at Peking Union Medical College Hospital between June and October 2025.CNCP was diagnosed based on the Neuropathic Pain Special Interest Group(NeuPSIG)criteria.Patients were classified into the CNCP group if they met at least one of the four NeuPSIG criteria,regardless of coexisting visceral or bone pain.Demographic,oncologic,and pain-related data were collected through standardized interviews.Between-group differences in baseline characteristics were assessed using absolute standardized differences and Chi-square or t-tests.Logistic regression analyses were conducted to identify clinical factors associated with CNCP.Results Of 138 eligible patients with CCP,85(61.6%)were classified into the CNCP group and 53(38.4%)into the non-CNCP group.Multivariable logistic regression analysis revealed that bone metastasis(adjusted OR=2.316,95%CI:1.074-5.178,P=0.032),radiotherapy(adjusted OR=2.489,95%CI:1.119-5.803,P=0.025),and voiding dysfunction(adjusted OR=5.470,95%CI:2.150-16.396,P<0.001)were independently associated with CNCP.Pancreatic cancer was inversely associated with CNCP(OR=0.371,P=0.031).Only 5(3.6%)patients in the CNCP group received neuropathic pain-specific interventions,indicating a predominant reliance on single-modality pain management.Conclusions CNCP was present in nearly two-thirds of outpatients with CCP.The identified associations with bone metastasis,radiotherapy,and voiding dysfunction may aid in the early recognition of neuropathic pain components and support the adoption of mechanism-based multimodal pain management strategies.展开更多
BACKGROUND Treatment of diabetic neuropathy is often limited by side effects.Aucubin,an iridoid glycoside derived from natural plants,exhibits notable anti-inflammatory and antioxidant properties.AIM To investigate th...BACKGROUND Treatment of diabetic neuropathy is often limited by side effects.Aucubin,an iridoid glycoside derived from natural plants,exhibits notable anti-inflammatory and antioxidant properties.AIM To investigate the effects of aucubin on diabetic neuropathic pain(DNP)and glycolysis and inflammation in microglia.METHODS Streptozotocin(STZ)was used to establish a DNP animal model.Blood glucose levels and body weight of mice were measured following STZ administration.Paw withdrawal threshold was calculated for mechanical allodynia.Paw withdrawal latency was recorded for thermal hyperalgesia.The open field test and elevated plus maze was used to assess locomotor activity and anxiety-like behavior.Western blotting was utilized for analysis of protein expression.Immunofluorescence staining was measured for morphometric analysis of microglia.Glycolysis and ATP synthesis in BV-2 cell lines were detected by metabolic extracellular flux analysis.The SwissTargetPrediction and STRING databases were used for comprehensive screening to identify potential target proteins for aucubin.The molecular docking between the possible target proteins and aucubin was investigated using Auto Dock Tool.The BV-2 cell line was transfected with lentiviral AKR1B1-shRNA to further ascertain the function of AKR1B1 in the impact of aucubin on aerobic glycolysis and inflammation during high glucose stimulation.RESULTS Aucubin significantly improved pain and anxiety-like behavior in STZ-induced diabetic mice and restored microglial aerobic glycolysis and inflammation.Several public databases and molecular docking studies suggested that AKR1B1,MMP2 and MMP9 are involved in the effect of aucubin on DNP.Aucubin failed to restore aerobic glycolysis and inflammation in the context of AKR1B1 deficiency.CONCLUSION Aucubin has potential as a therapeutic agent for alleviating DNP by inhibiting expression of AKR1B1.展开更多
This letter critically comments on the article by Zheng et al investigating the role of aucubin in alleviating diabetic neuropathic pain(DNP).DNP arises from hyperglycaemia-induced nerve injury and microglial reprogra...This letter critically comments on the article by Zheng et al investigating the role of aucubin in alleviating diabetic neuropathic pain(DNP).DNP arises from hyperglycaemia-induced nerve injury and microglial reprogramming toward aerobic glycolysis.Aldose reductase(also known as AKR1B1)redirects excess glucose flux through the polyol pathway,thus increasing oxidative stress and inflammation.Zheng et al show that aucubin,a plant iridoid glycoside,reverses streptozotocin-induced mechanical and thermal hypersensitivity and anxiety-like behaviour in mice.Mechanistically,aucubin restores microglial morphology,reduces glycolytic flux,enhances oxidative phosphorylation and lowers tumour necrosis factor-α,interleukin(IL)-1βand IL-6 levels in spinal tissue and cultures of the BV-2 microglial cell line.Network pharmacology and molecular docking analyses identify AKR1B1 as a key target,confirmed by the fact that short hairpin RNA knockdown of AKR1B1 eliminates the effects of aucubin.Contrary to the other studies,this study uniquely implicates the polyol pathway in microglial immunometabolism.展开更多
Background:Neuropathic pain(NP)has a long course and is difficult to treat,causing great physical suffering and psychological burden to patients.Unfortunately,the pathogenesis of NP is still poorly understood.The occu...Background:Neuropathic pain(NP)has a long course and is difficult to treat,causing great physical suffering and psychological burden to patients.Unfortunately,the pathogenesis of NP is still poorly understood.The occurrence and progression of NP are influenced by microRNA(miRNA).It has been reported that Tuina may effectively alleviate NP,however,the mechanisms related to miRNA-mediated Tuina for NP are still unexplored.Methods:To generate NP,a rat model of chronic constriction injury(CCI)was developed.Rats’pain thresholds are studied through pain behaviour tests.The effect of Tuina on the structure and morphology of neurones in the spinal dorsal horn(SDH)of rats with neuropathological pain was examined using HE staining.The levels of miRNA in the SDH of rats with a CCI model were studied using RNA sequencing(RNA-seq)and bioinformatics analysis.The top three miRNAs with the highest fold changes were chosen for qRT-PCR detection to confirm the validity of the RNA-seq results.Results:On the 4th day after CCI surgery,the paw withdrawal threshold(PWT)of the CCI+Tuina group was considerably higher than that of the CCI group(P<0.001).Furthermore,there was a significant increase in the paw withdrawal latency(PWL)of the CCI+Tuina group from day 4 to day 17 after the CCI surgery(P<0.001).Differentially expressed miRNAs in the SDH of three groups of rats were examined using RNA-seq technology.Seven miRNAs were found to intersect in total.The Kyoto Encyclopaedia of Genes and Genomes(KEGG)and Gene Ontology(GO)both anticipated the possible roles of the miRNAs.The RNA-seq results matched the changes in the levels of miR-383-3p(P<0.01),miR-183-3p(P<0.01),and miR-184(P<0.01).Conclusion:CCI-induced NP in rats leads to changes in miRNA expression in the SDH,and Tuina may alleviate NP by modulating the expression pattern of miRNAs and their underlying mechanisms.These findings may provide new targets for future NP treatment.展开更多
Background:Existing remedial approaches for relieving neuropathic pain(NPP)are challenging and open the way for alternative therapeutic measures such as electroacupuncture(EA).The mechanism underlying the antinocicept...Background:Existing remedial approaches for relieving neuropathic pain(NPP)are challenging and open the way for alternative therapeutic measures such as electroacupuncture(EA).The mechanism underlying the antinociceptive effects of repeated EA sessions,particularly concerning the regulation of the Adora3 receptor and its associated enzymes,has remained elusive.Methods:This study used a mouse model of spared nerve injury(SNI)to explore the cumulative analgesic effects of repeated EA at ST36(Zusanli)and its impact on Adora3 regulation in the spinal cord dorsal horn(SCDH).Forty-eight male mice underwent SNI surgery for induction of neuropathic pain and were randomly assigned to the SNI,SNI+2EA,SNI+4EA,and SNI+7EA groups.Spinal cord(L4-L6)was sampled for immunofluorescence,adenosine(ADO)detection and for molecular investigations following repeated EA treatment.Results:Following spared nerve injury(SNI),there was a significant decrease in mechanical withdrawal thresholds(PWTs)and thermal nociceptive withdrawal latency(TWL)in the ipsilateral hind paw on the third day post-surgery,while the contralateral hind paw PWTs showed no significant changes.On subsequent EA treatments,the SNI+EA groups led to a significant increase in pain thresholds(p<0.05).Repeated EA sessions in SNI mice upregulated Adenosine A3(Adora3)and cluster of differentiation-73(CD73)expression while downregulating adenosine deaminase(ADA)and enhancing neuronal instigation in the SCDH.Colocalization analysis of Neun-treated cells revealed increased Adora3 expression,particularly in the SNI+7EA group.Conclusions:In conclusion,cumulative electroacupuncture treatment reduced neuropathic pain by regulating Adora3 and CD73 expression,inhibiting ADA and most likely increasing neuronal activation in the SCDH.This study offers a promising therapeutic option for managing neuropathic pain,paving the way for further research.展开更多
BACKGROUND Chronic neuropathic pain and depression are common and debilitating conditions in cancer patients,significantly impacting their quality of life.Pregabalin,an anticonvulsant medication,is used for neuropathi...BACKGROUND Chronic neuropathic pain and depression are common and debilitating conditions in cancer patients,significantly impacting their quality of life.Pregabalin,an anticonvulsant medication,is used for neuropathic pain and may also influence depressive symptoms.This study evaluates the efficacy and safety of pregabalin on pain intensity,depression severity,and side effects in cancer patients with chronic neuropathic pain and depression.AIM To evaluate the impact of pregabalin on pain intensity,depression severity,and the safety profile in cancer patients with chronic neuropathic pain and depression.METHODS This observational case series included 10 cancer patients experiencing chronic neuropathic pain and depression.Pregabalin was administered at a starting dose of 150 mg twice daily,with adjustments based on patient tolerance and pain response up to 300 mg twice daily.Pain intensity and depression severity were assessed using the brief pain inventory(BPI)and the Hamilton depression rating scale(HDRS)at baseline,4 weeks,and 8 weeks.Side effects were monitored using a self-reported side effect questionnaire.RESULTS Pregabalin led to a significant reduction in pain intensity and depression severity.The mean BPI score decreased from 7.8(SD=1.2)at baseline to 5.2(SD=1.4)at 4 weeks and 4.1(SD=1.5)at 8 weeks,representing reductions of 33.3%and 47.4%,respectively.The mean HDRS score decreased from 18.5(SD=4.0)at baseline to 13.2(SD=4.1)at 4 weeks and 9.8(SD=3.6)at 8 weeks,showing reductions of 28.4%and 47.0%,respectively.Side effects included dizziness(50%),drowsiness(40%),weight gain(30%),and dry mouth(20%).No severe adverse effects were reported.All patients completed the study,with 30%requiring dose adjustments.CONCLUSION Pregabalin significantly alleviates both chronic neuropathic pain and depression in cancer patients with a manageable safety profile.These findings support the use of pregabalin in this patient population,though further research with larger samples and controlled designs is warranted.展开更多
Neuropathic pain(NP)is one of the most common pathological pain types and is associated with limited treatment options;moreover,it affects patients’quality of life and causes a heavy social burden.Despite the emphasi...Neuropathic pain(NP)is one of the most common pathological pain types and is associated with limited treatment options;moreover,it affects patients’quality of life and causes a heavy social burden.Despite the emphasis on inhibiting neuronal apoptosis to relieve NP,the crucial role of a neuroinflammation is often overlooked.Therefore,refocusing on the regulation of microglia polarization to create a more conducive environment for neuron holds great potential in NP treatment.In recent years,small interfering RNAs(siRNAs)had become an attractive therapeutic option.However,an efficient loading and delivery system for siRNA is still in lack.In our study,a nanostructured tetrahedral framework nucleic acid loaded with the small interfering RNA C–C chemokine receptor 2(T-siCCR2)was successfully designed and synthesized for use in NP rat model in vivo and in a lipopolysaccharide(LPS)-induced inflammatory environment in vitro.This nanoscale complex is endowed with structural stability and satisfactory delivery efficiency while assuring the silencing effect of siRNA-CCR2.In vivo,T-siCCR2 treatment exhibited favorable effects on pain relief and functional improvement in the NP animal model by directly targeting microglia.In vitro,T-siCCR2 counteracts LPS-induced inflammation by inhibiting the differentiation of microglia toward the M1 phenotype,thus playing a neuroprotective role.RNA sequencing was subsequently performed to elucidate the underlying mechanism involved.These results indicate that T-siCCR2 may serve as a potential treatment option for NP in the future.展开更多
Cisplatin chemotherapy has been used as the main treatment for different types of cancer.However,cisplatin chemotherapy-induced peripheral neuropathic pain(CIPNP)seriously affects the treatment process and quality of ...Cisplatin chemotherapy has been used as the main treatment for different types of cancer.However,cisplatin chemotherapy-induced peripheral neuropathic pain(CIPNP)seriously affects the treatment process and quality of life of patients.In addition,it impacts the underlying mechanism and prevention and treatment strategies,indicating that drug selection and efficacy evaluation need to be further investigated.Furthermore,an animal model that is more consistent with the pathological mechanism needs to be developed.In this study,we describe and discuss the methods of developing and detecting CIPNP models in rats and mice induced by cisplatin chemotherapy.The aim was to improve the modeling rate and develop animal models that are more consistent with the developmental pattern of the disease.In addition,the study provides ideal reference animal models for clinical research and drug discovery and development.展开更多
Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsol...Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.展开更多
This research study focuses on addressing the limitations of current neuropathic pain(NP)treatments by developing a novel dual-target modulator,E0199,targeting both Na_(V)1.7,Na_(V)1.8,and Na_(V)1.9 and K_(V)7 channel...This research study focuses on addressing the limitations of current neuropathic pain(NP)treatments by developing a novel dual-target modulator,E0199,targeting both Na_(V)1.7,Na_(V)1.8,and Na_(V)1.9 and K_(V)7 channels,a crucial regulator in controlling NP symptoms.The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP.Through an experimental design involving both in vitro and in vivo methods,E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury(CCI)mouse model.The results demonstrated that E0199 significantly inhibited Na_(V)1.7,Na_(V)1.8,and Na_(V)1.9 channels with a particularly low half maximal inhibitory concentration(IC50)for Na_(V)1.9 by promoting sodium channel inactivation,and also effectively increased K_(V)7.2/7.3,K_(V)7.2,and K_(V)7.5 channels,excluding K_(V)7.1 by promoting potassium channel activation.This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses,indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically.The safety of E0199 was supported by neurobehavioral evaluations.Conclusively,E0199 represents a ground-breaking approach in NP treatment,showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP.This study introduces a promising direction for the future development of NP therapeutics.展开更多
Objective The present study aimed to investigate the electrophysiological properties of wide dynamic range （WDR） neurons in spinal dorsal horn of rats with neuropathic pain induced by lumber 5 （L5） spinal nerve li...Objective The present study aimed to investigate the electrophysiological properties of wide dynamic range （WDR） neurons in spinal dorsal horn of rats with neuropathic pain induced by lumber 5 （L5） spinal nerve ligation （SNL） in a large size of samples.Methods Adult Sprague-Dawley rats were divided into normal and SNL groups.Electrophysiological technique was used to record the characteristics of WDR neurons in the spinal dorsal horn.Results Compared with the WDR neurons in normal rats,the WDR neurons in SNL rats showed an increase in excitability,manifested by an enlargement of the receptive field size,an increase in the proportion of neurons that exhibited spontaneous activities,decreases in the Cresponse threshold and latency,and an increase in the C-response duration.In addition,the numbers of A-and C-fiberevoked discharges were smaller in SNL rats than in normal rats.Conclusion The excitability of spinal WDR neurons increased in rats with neuropathic pain induced by L5 SNL.The increase in excitability of WDR neurons may contribute to the development of neuropathic pain.展开更多
Electroacupuncture has traditionally been used to treat pain, but its effect on pain following brachial plexus injury is still unknown. In this study, rat models of an avulsion injury to the left brachial plexus root ...Electroacupuncture has traditionally been used to treat pain, but its effect on pain following brachial plexus injury is still unknown. In this study, rat models of an avulsion injury to the left brachial plexus root （associated with upper-limb chronic neuropathic pain） were given electroacupuncture stimulation at bilateral Quchi （LIll）, Hegu （LI04）, Zusanli （ST36） and Yanglingquan （GB34）. After electroacupuncture therapy, chronic neuropathic pain in the rats＇ upper limbs was significantly attenuated. Immunofluorescence staining showed that the expression of β-endorphins in the arcuate nucleus was significantly increased after therapy. Thus, experimental findings indi- cate that electroacupuncture can attenuate neuropathic pain after brachial plexus injury through upregulating β-endorphin expression.展开更多
Neuropathic pain(NP)has become a serious global health issue and a huge clinical challenge without available effective treatment.P2 receptors family is involved in pain transmission and represents a promising target f...Neuropathic pain(NP)has become a serious global health issue and a huge clinical challenge without available effective treatment.P2 receptors family is involved in pain transmission and represents a promising target for pharmacological intervention.Traditional Chinese medicine(TCM)contains multiple components which are effective in targeting different pathological mechanisms involved in NP.Different from traditional analgesics,which target a single pathway,TCMs take the advantage of multiple components and multiple targets,and can significantly improve the efficacy of treatment and contribute to the prediction of the risks of NP.Compounds of TCM acting at nucleotide P2 receptors in neurons and glial cells could be considered as a potential research direction for moderating neuropathic pain.This review summarized the recently published data and highlighted several TCMs that relieved NP by acting at P2 receptors.展开更多
Diabetic neuropathy is a common complication of both type 1 and type 2 diabetes,which affects over 90% of the diabetic patients.Although pain is one of the main symptoms of diabetic neuropathy,its pathophysiological m...Diabetic neuropathy is a common complication of both type 1 and type 2 diabetes,which affects over 90% of the diabetic patients.Although pain is one of the main symptoms of diabetic neuropathy,its pathophysiological mechanisms are not yet fully known.It is widely accepted that the toxic effects of hyperglycemia play an important role in the development of this complication,but several other hypotheses have been postulated.The management of diabetic neuropathic pain consists basically in excluding other causes of painful peripheral neuropathy,improving glycemic control as a prophylactic therapy and using medications to alleviate pain.First line drugs for pain relief include anticonvulsants,such as pregabalin and gabapentin and antidepressants,especial y those that act to inhibit the reuptake of serotonin and noradrenaline.In addition,there is experimental and clinical evidence that opioids can be helpful in pain control,mainly if associated with first line drugs.Other agents,including for topical application,such as capsaicin cream and lidocaine patches,have also been proposed to be useful as adjuvants in the control of diabetic neuropathic pain,but the clinical evidence is insufficient to support their use.In conclusion,a better understanding of the mechanisms underlying diabetic neuropathic pain will contribute to the search of new therapies,but also to the improvement of the guidelines to optimize pain control with the drugs currently available.展开更多
Emerging evidence indicates that CXCL12/ CXCR4 signaling is involved in chronic pain. However, few studies have systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mech- a...Emerging evidence indicates that CXCL12/ CXCR4 signaling is involved in chronic pain. However, few studies have systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mech- anism. Here, we determined that spared nerve injury （SNI） increased the expression of CXCL12 and its cognate receptor CXCR4 in lumbar 5 dorsal root ganglia （DRG） neurons and satellite glial cells. SNI also induced long- lasting upregulation of CXCL12 and CXCR4 in the ipsi- lateral L4-5 spinal cord dorsal horn, characterized by CXCL12 expression in neurons and microglia, and CXCR4 expression in neurons and astrocytes. Moreover, SNI- induced a sustained increase in TNF-α expression in the DRG and spinal cord. Intraperitoneal injection （i.p.） of the TNF-α synthesis inhibitor thalidomide reduced the SNI-in- duced mechanical hypersensitivity and inhibited the expression of CXCL12 in the DRG and spinal cord. Intrathecal injection （i.t.） of the CXCR4 antagonist AMD3100, both 30 rain before and 7 days after SNI, reduced the behavioral signs of allodynia. Rats given an i.t. or i.p. bolus of AMD3100 on day 8 of SNI exhibited attenuated abnormal pain behaviors. The neuropathic pain established following SNI was also impaired by i.t. admin- istration of a CXCL12-neutralizing antibody. Moreover, repetitive i.t. AMD3100 administration prevented the acti- vation of ERK in the spinal cord. The mechanical hyper- sensitivity induced in nai＇ve rats by i.t. CXCL12 was alleviated by pretreatment with the MEK inhibitor PD98059. Collectively, our results revealed that TNF-α might mediate the upregulation of CXCL12 in the DRG and spinal cord following SNI, and that CXCL 12/CXCR4 sig- naling via ERK activation contributes to the development and maintenance of neuropathic pain.展开更多
Pain consists of sensory-discriminative and emotional-affective components.The anterior cingulate cortex(ACC)is a critical brain area in mediating the affective pain.However,the molecular mechanisms involved remain la...Pain consists of sensory-discriminative and emotional-affective components.The anterior cingulate cortex(ACC)is a critical brain area in mediating the affective pain.However,the molecular mechanisms involved remain largely unknown.Our recent study indicated that C-X-C motif chemokine 13(CXCL13)and its sole receptor CXCR5 are involved in sensory sensitization in the spinal cord after spinal nerve ligation(SNL).Whether CXCL13/CXCR5 signaling in the ACC contributes to the pathogenesis of pain-related aversion remains unknown.Here,we showed that SNL increased the CXCL13 level and CXCR5 expression in the ACC after SNL.Knockdown of CXCR5 by microinjection of Cxcr5 shRNA into the ACC did not affect SNL-induced mechanical allodynia but effectively alleviated neuropathic painrelated place avoidance behavior.Furthermore,electrophysiological recording from layer Ⅱ-Ⅲ neurons in the ACC showed that SNL increased the frequency and amplitude of spontaneous excitatory postsynaptic currents(sEPSCs),decreased the EPSC paired-pulse ratio,and increased the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor ratio,indicating enhanced glutamatergic synaptic transmission.Finally,superfusion of CXCL13 onto ACC slices increased the frequency and amplitude of spontaneous EPSCs.Pre-injection of Cxcr5 shRNA into the ACC reduced the increase in glutamatergic synaptic transmis sion induced by SNL.Collectively,these results suggest that CXCL13/CXCR5 signaling in the ACC is involved in neuropathic pain-related aversion via synaptic potentiation.展开更多
基金supported by the National Natural Science Foundation of China(82474625)Zhejiang Provincial Natural Science Funds(LZ23H270001).
文摘In a recent work published in Neuron,Xu et al.identified a novel contribution of G protein-coupled receptor 37-like 1(GPR37L1),which is identified to be expressed by spinal astrocytes,to the regulation of neuropathic pain[1].By interacting and enhancing the activity of glutamate transporter-1(GLT-1)in spinal astrocytes,GPR37L1 promotes glutamate uptake by spinal astrocytes and reduces excitatory synaptic transmission in the spinal dorsal horn,all of which contribute to the resolution of chronic neuropathic pain.
基金supported by the National Natural Science Foundation of China,Nos.82001178(to LW),81901129(to LH),82001175(to FX)Shanghai Sailing Program,No.20YF1439200(to LW)+1 种基金the Natural Science Foundation of Shanghai,China,No.23ZR1450800(to LH)and the Fundamental Research Funds for the Central Universities,No.YG2023LC15(to ZX)。
文摘Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this effect.In this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic analysis.The results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer pain.In addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain hypersensitivity.Furthermore,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression.Moreover,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was enhanced.Mechanistically,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F.Additionally,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 methylation.These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.
基金supported by the National Natural Science Foundation of China(82071249 and 81771207).
文摘Objective:Neuropathic pain(NP)is one of the most common forms of chronic pain,yet current treatment options are limited in effectiveness.Peripheral nerve injury activates spinal microglia,altering their inflammatory response and phagocytic functions,which contributes to the progression of NP.Most current research on NP focuses on microglial inflammation,with relatively little attention to their phagocytic function.Early growth response factor 2(EGR2)has been shown to regulate microglial phagocytosis,but its specific role in NP remains unclear.This study aims to investigate how EGR2 modulates microglial phagocytosis and its involvement in NP,with the goal of identifying potential therapeutic targets.Methods:Adult male Sprague-Dawley(SD)rats were used to establish a chronic constriction injury(CCI)model of the sciatic nerve.Pain behaviors were assessed on days 1,3,7,10,and 14 post-surgery to confirm successful model induction.The temporal and spatial expression of EGR2 in the spinal cord was examined using real-time quantitative PCR(RT-qPCR),Western blotting,and immunofluorescence staining.Adeno-associated virus(AAV)was used to overexpress EGR2 in the spinal cord,and behavioral assessments were performed to evaluate the effects of EGR2 modulation of NP.CCI and lipopolysaccharide(LPS)models were established in animals and microglial cell lines,respectively,and changes in phagocytic activity were measured using RT-qPCR and fluorescent latex bead uptake assays.After confirming the involvement of microglial phagocytosis in NP,AAV was used to overexpress EGR2 in both in vivo and in vitro models,and phagocytic activity was further evaluated.Finally,eukaryotic transcriptome sequencing was conducted to screen differentially expressed mRNAs,followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses to identify potential downstream effectors of EGR2.Results:The CCI model successfully induced NP.Following CCI,EGR2 expression in the spinal cord was upregulated in parallel with NP development.Overexpression of EGR2 via spinal AAV injection enhanced microglial phagocytic activity and increased pain hypersensitivity in rats.Both animal and cellular models showed that CCI or LPS stimulation enhanced microglial phagocytosis,which was further amplified by EGR2 overexpression.Transcriptomic analysis of spinal cord tissues from CCI rats overexpressing EGR2 revealed upregulation of numerous genes associated with microglial phagocytosis and pain regulation.Among them,Lag3 emerged as a potential downstream target of EGR2.Conclusion:EGR2 contributes to the maintenance of NP by enhancing microglial phagocytosis in the spinal dorsal horn.
文摘Objective To explore the therapeutic effect of LuoFuShan Rheumatism Plaster(LFS)on neuropathic pain(NP)and its molecular mechanism.Methods Mouse models of sciatic nerve chronic constriction injury(CCI)were treated with low,medium,and high doses(2.2,4.4,and 8.8 cm2,respectively)of LFS by topical application for 14 consecutive days.The therapeutic effects were assessed by evaluating the mechanical withdrawal threshold(MWT),paw withdrawal latency(PWL),plasma IL-6 and TNF-αlevels,and histopathology of the sciatic nerve.Network pharmacology and molecular docking were used to identify the key targets and signaling pathways.The key targets were verified by RT-qPCR and immunohistochemistry.The biosafety of LFS was evaluated by measuring the organ indices and damage indicators of the heart,liver,and kidneys.Results Compared with the CCI group,LFS dose-dependently increased MWT and PWL,reduced plasma IL-6 and TNF-αlevels,and alleviated sciatic nerve inflammation in the mouse models.Network pharmacology identified 378 bioactive compounds targeting 279 NPassociated genes enriched in TLR and TNF signaling.Molecular docking showed that quercetin and ursolic acid in LFS could stably bind to TLR4 and TNF-α.In the mouse models of sciatic nerve CCI,LFS significantly downregulated the mRNA expression levels of Tlr4 and Tnf-αin the spinal cord in a dose-dependent manner and lowered the protein expressions of TLR4 and TNF-αin the sciatic nerve.LFS treatment did not cause significant changes in the organ indices or damage indicators of the heart,liver and kidneys as compared with those in the CCI model group and sham-operated group.Conclusion LFS alleviates NP in mice by suppression of TLR4/TNF-α-mediated neuroinflammation with a good safety profile.
文摘Objective To determine the prevalence,distribution,and associated clinical factors of chronic neuropathic cancer pain(CNCP)among outpatients with chronic cancer pain(CCP)and to inform improved recognition and management.Methods In this cross-sectional study,consecutive outpatients with CCP diagnosed according to the International Association for the Study of Pain(IASP)criteria were recruited from the pain clinic at Peking Union Medical College Hospital between June and October 2025.CNCP was diagnosed based on the Neuropathic Pain Special Interest Group(NeuPSIG)criteria.Patients were classified into the CNCP group if they met at least one of the four NeuPSIG criteria,regardless of coexisting visceral or bone pain.Demographic,oncologic,and pain-related data were collected through standardized interviews.Between-group differences in baseline characteristics were assessed using absolute standardized differences and Chi-square or t-tests.Logistic regression analyses were conducted to identify clinical factors associated with CNCP.Results Of 138 eligible patients with CCP,85(61.6%)were classified into the CNCP group and 53(38.4%)into the non-CNCP group.Multivariable logistic regression analysis revealed that bone metastasis(adjusted OR=2.316,95%CI:1.074-5.178,P=0.032),radiotherapy(adjusted OR=2.489,95%CI:1.119-5.803,P=0.025),and voiding dysfunction(adjusted OR=5.470,95%CI:2.150-16.396,P<0.001)were independently associated with CNCP.Pancreatic cancer was inversely associated with CNCP(OR=0.371,P=0.031).Only 5(3.6%)patients in the CNCP group received neuropathic pain-specific interventions,indicating a predominant reliance on single-modality pain management.Conclusions CNCP was present in nearly two-thirds of outpatients with CCP.The identified associations with bone metastasis,radiotherapy,and voiding dysfunction may aid in the early recognition of neuropathic pain components and support the adoption of mechanism-based multimodal pain management strategies.
基金Supported by National Natural Science Foundation of China,No.82001424.
文摘BACKGROUND Treatment of diabetic neuropathy is often limited by side effects.Aucubin,an iridoid glycoside derived from natural plants,exhibits notable anti-inflammatory and antioxidant properties.AIM To investigate the effects of aucubin on diabetic neuropathic pain(DNP)and glycolysis and inflammation in microglia.METHODS Streptozotocin(STZ)was used to establish a DNP animal model.Blood glucose levels and body weight of mice were measured following STZ administration.Paw withdrawal threshold was calculated for mechanical allodynia.Paw withdrawal latency was recorded for thermal hyperalgesia.The open field test and elevated plus maze was used to assess locomotor activity and anxiety-like behavior.Western blotting was utilized for analysis of protein expression.Immunofluorescence staining was measured for morphometric analysis of microglia.Glycolysis and ATP synthesis in BV-2 cell lines were detected by metabolic extracellular flux analysis.The SwissTargetPrediction and STRING databases were used for comprehensive screening to identify potential target proteins for aucubin.The molecular docking between the possible target proteins and aucubin was investigated using Auto Dock Tool.The BV-2 cell line was transfected with lentiviral AKR1B1-shRNA to further ascertain the function of AKR1B1 in the impact of aucubin on aerobic glycolysis and inflammation during high glucose stimulation.RESULTS Aucubin significantly improved pain and anxiety-like behavior in STZ-induced diabetic mice and restored microglial aerobic glycolysis and inflammation.Several public databases and molecular docking studies suggested that AKR1B1,MMP2 and MMP9 are involved in the effect of aucubin on DNP.Aucubin failed to restore aerobic glycolysis and inflammation in the context of AKR1B1 deficiency.CONCLUSION Aucubin has potential as a therapeutic agent for alleviating DNP by inhibiting expression of AKR1B1.
基金Supported by the Top-level Talents Support Program of Yangzhou University“Lv Yang Jin Feng”Outstanding Doctor of Yangzhou,No.YZLYJFJH2023YXBS169Natural Science Foundation of Jiangsu Province,No.BK20240907.
文摘This letter critically comments on the article by Zheng et al investigating the role of aucubin in alleviating diabetic neuropathic pain(DNP).DNP arises from hyperglycaemia-induced nerve injury and microglial reprogramming toward aerobic glycolysis.Aldose reductase(also known as AKR1B1)redirects excess glucose flux through the polyol pathway,thus increasing oxidative stress and inflammation.Zheng et al show that aucubin,a plant iridoid glycoside,reverses streptozotocin-induced mechanical and thermal hypersensitivity and anxiety-like behaviour in mice.Mechanistically,aucubin restores microglial morphology,reduces glycolytic flux,enhances oxidative phosphorylation and lowers tumour necrosis factor-α,interleukin(IL)-1βand IL-6 levels in spinal tissue and cultures of the BV-2 microglial cell line.Network pharmacology and molecular docking analyses identify AKR1B1 as a key target,confirmed by the fact that short hairpin RNA knockdown of AKR1B1 eliminates the effects of aucubin.Contrary to the other studies,this study uniquely implicates the polyol pathway in microglial immunometabolism.
基金supported by the Project of National Natural Science Foundation of China(No.82174523,No.82205303)Fujian Provincial Health Commission Traditional Chinese Medicine Science and Technology Plan Project(No.2025YBB010)Natural Science Foundation of Fujian Province(No.2023J06037,No.2024J01141).
文摘Background:Neuropathic pain(NP)has a long course and is difficult to treat,causing great physical suffering and psychological burden to patients.Unfortunately,the pathogenesis of NP is still poorly understood.The occurrence and progression of NP are influenced by microRNA(miRNA).It has been reported that Tuina may effectively alleviate NP,however,the mechanisms related to miRNA-mediated Tuina for NP are still unexplored.Methods:To generate NP,a rat model of chronic constriction injury(CCI)was developed.Rats’pain thresholds are studied through pain behaviour tests.The effect of Tuina on the structure and morphology of neurones in the spinal dorsal horn(SDH)of rats with neuropathological pain was examined using HE staining.The levels of miRNA in the SDH of rats with a CCI model were studied using RNA sequencing(RNA-seq)and bioinformatics analysis.The top three miRNAs with the highest fold changes were chosen for qRT-PCR detection to confirm the validity of the RNA-seq results.Results:On the 4th day after CCI surgery,the paw withdrawal threshold(PWT)of the CCI+Tuina group was considerably higher than that of the CCI group(P<0.001).Furthermore,there was a significant increase in the paw withdrawal latency(PWL)of the CCI+Tuina group from day 4 to day 17 after the CCI surgery(P<0.001).Differentially expressed miRNAs in the SDH of three groups of rats were examined using RNA-seq technology.Seven miRNAs were found to intersect in total.The Kyoto Encyclopaedia of Genes and Genomes(KEGG)and Gene Ontology(GO)both anticipated the possible roles of the miRNAs.The RNA-seq results matched the changes in the levels of miR-383-3p(P<0.01),miR-183-3p(P<0.01),and miR-184(P<0.01).Conclusion:CCI-induced NP in rats leads to changes in miRNA expression in the SDH,and Tuina may alleviate NP by modulating the expression pattern of miRNAs and their underlying mechanisms.These findings may provide new targets for future NP treatment.
基金National Natural Science Foundation of China,Grant/Award Number:32172930。
文摘Background:Existing remedial approaches for relieving neuropathic pain(NPP)are challenging and open the way for alternative therapeutic measures such as electroacupuncture(EA).The mechanism underlying the antinociceptive effects of repeated EA sessions,particularly concerning the regulation of the Adora3 receptor and its associated enzymes,has remained elusive.Methods:This study used a mouse model of spared nerve injury(SNI)to explore the cumulative analgesic effects of repeated EA at ST36(Zusanli)and its impact on Adora3 regulation in the spinal cord dorsal horn(SCDH).Forty-eight male mice underwent SNI surgery for induction of neuropathic pain and were randomly assigned to the SNI,SNI+2EA,SNI+4EA,and SNI+7EA groups.Spinal cord(L4-L6)was sampled for immunofluorescence,adenosine(ADO)detection and for molecular investigations following repeated EA treatment.Results:Following spared nerve injury(SNI),there was a significant decrease in mechanical withdrawal thresholds(PWTs)and thermal nociceptive withdrawal latency(TWL)in the ipsilateral hind paw on the third day post-surgery,while the contralateral hind paw PWTs showed no significant changes.On subsequent EA treatments,the SNI+EA groups led to a significant increase in pain thresholds(p<0.05).Repeated EA sessions in SNI mice upregulated Adenosine A3(Adora3)and cluster of differentiation-73(CD73)expression while downregulating adenosine deaminase(ADA)and enhancing neuronal instigation in the SCDH.Colocalization analysis of Neun-treated cells revealed increased Adora3 expression,particularly in the SNI+7EA group.Conclusions:In conclusion,cumulative electroacupuncture treatment reduced neuropathic pain by regulating Adora3 and CD73 expression,inhibiting ADA and most likely increasing neuronal activation in the SCDH.This study offers a promising therapeutic option for managing neuropathic pain,paving the way for further research.
文摘BACKGROUND Chronic neuropathic pain and depression are common and debilitating conditions in cancer patients,significantly impacting their quality of life.Pregabalin,an anticonvulsant medication,is used for neuropathic pain and may also influence depressive symptoms.This study evaluates the efficacy and safety of pregabalin on pain intensity,depression severity,and side effects in cancer patients with chronic neuropathic pain and depression.AIM To evaluate the impact of pregabalin on pain intensity,depression severity,and the safety profile in cancer patients with chronic neuropathic pain and depression.METHODS This observational case series included 10 cancer patients experiencing chronic neuropathic pain and depression.Pregabalin was administered at a starting dose of 150 mg twice daily,with adjustments based on patient tolerance and pain response up to 300 mg twice daily.Pain intensity and depression severity were assessed using the brief pain inventory(BPI)and the Hamilton depression rating scale(HDRS)at baseline,4 weeks,and 8 weeks.Side effects were monitored using a self-reported side effect questionnaire.RESULTS Pregabalin led to a significant reduction in pain intensity and depression severity.The mean BPI score decreased from 7.8(SD=1.2)at baseline to 5.2(SD=1.4)at 4 weeks and 4.1(SD=1.5)at 8 weeks,representing reductions of 33.3%and 47.4%,respectively.The mean HDRS score decreased from 18.5(SD=4.0)at baseline to 13.2(SD=4.1)at 4 weeks and 9.8(SD=3.6)at 8 weeks,showing reductions of 28.4%and 47.0%,respectively.Side effects included dizziness(50%),drowsiness(40%),weight gain(30%),and dry mouth(20%).No severe adverse effects were reported.All patients completed the study,with 30%requiring dose adjustments.CONCLUSION Pregabalin significantly alleviates both chronic neuropathic pain and depression in cancer patients with a manageable safety profile.These findings support the use of pregabalin in this patient population,though further research with larger samples and controlled designs is warranted.
基金supported by National Natural Science Foundation of China(Nos.81874027,82370929,81970916)Sichuan Science and Technology Program(Nos.2019YFQ0003,2022YFS0051,2022NSFSC0002)+3 种基金Sichuan Province Youth Science and Technology Innovation Team(No.2022JDTD0021)Research and Develop Program,West China Hospital of Stomatology Sichuan University(Nos.RD03202302,RCDWJS2024–1)135-project for disciplines of excellenceClinical Research Incubation project of West China Hospital of Sichuan University(No.2021HXFH036)。
文摘Neuropathic pain(NP)is one of the most common pathological pain types and is associated with limited treatment options;moreover,it affects patients’quality of life and causes a heavy social burden.Despite the emphasis on inhibiting neuronal apoptosis to relieve NP,the crucial role of a neuroinflammation is often overlooked.Therefore,refocusing on the regulation of microglia polarization to create a more conducive environment for neuron holds great potential in NP treatment.In recent years,small interfering RNAs(siRNAs)had become an attractive therapeutic option.However,an efficient loading and delivery system for siRNA is still in lack.In our study,a nanostructured tetrahedral framework nucleic acid loaded with the small interfering RNA C–C chemokine receptor 2(T-siCCR2)was successfully designed and synthesized for use in NP rat model in vivo and in a lipopolysaccharide(LPS)-induced inflammatory environment in vitro.This nanoscale complex is endowed with structural stability and satisfactory delivery efficiency while assuring the silencing effect of siRNA-CCR2.In vivo,T-siCCR2 treatment exhibited favorable effects on pain relief and functional improvement in the NP animal model by directly targeting microglia.In vitro,T-siCCR2 counteracts LPS-induced inflammation by inhibiting the differentiation of microglia toward the M1 phenotype,thus playing a neuroprotective role.RNA sequencing was subsequently performed to elucidate the underlying mechanism involved.These results indicate that T-siCCR2 may serve as a potential treatment option for NP in the future.
基金Liaoning Provincial Key Research and Development Program,Grant/Award Number:2024JH2/102500062China Health Promotion Foundation Spark Program,Grant/Award Number:XH-D001National Natural Science Foundation of China,Grant/Award Number:82104838。
文摘Cisplatin chemotherapy has been used as the main treatment for different types of cancer.However,cisplatin chemotherapy-induced peripheral neuropathic pain(CIPNP)seriously affects the treatment process and quality of life of patients.In addition,it impacts the underlying mechanism and prevention and treatment strategies,indicating that drug selection and efficacy evaluation need to be further investigated.Furthermore,an animal model that is more consistent with the pathological mechanism needs to be developed.In this study,we describe and discuss the methods of developing and detecting CIPNP models in rats and mice induced by cisplatin chemotherapy.The aim was to improve the modeling rate and develop animal models that are more consistent with the developmental pattern of the disease.In addition,the study provides ideal reference animal models for clinical research and drug discovery and development.
基金supported by the National Natural Science Foundation of China(81971058,82371226,82101295,82301398)the National Funded Postdoctoral Researcher Program(GZC20233585)The Boost Plan of Xijing Hospital(XJZT24QN25,XJZT25CX22).
文摘Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.
基金funded by the Key Project from the Hebei Provincial Department of Science and Technology,China(Grant No.:21372601D)the Foundation Postdoctoral Mobile Station of Basic Medical Sciences,Hebei Medical University,China(Grant No.:20123120019)+4 种基金the Natural Science Foundation of Hebei Province,China(Grant No.:H2021206352)the Science and Technology Research Project of Colleges and Universities in Hebei Province,China(Grant No.:QN2023197)Hebei Medical University,Science and Technology,China(Grant No.:CYQD2023014)Hebei Provincial Department of Human Resources and Social Security,China(Grant No.:B2023003034)the Consultative Foundation from Hebei Province,China(Grant No.:2020TXZH01).
文摘This research study focuses on addressing the limitations of current neuropathic pain(NP)treatments by developing a novel dual-target modulator,E0199,targeting both Na_(V)1.7,Na_(V)1.8,and Na_(V)1.9 and K_(V)7 channels,a crucial regulator in controlling NP symptoms.The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP.Through an experimental design involving both in vitro and in vivo methods,E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury(CCI)mouse model.The results demonstrated that E0199 significantly inhibited Na_(V)1.7,Na_(V)1.8,and Na_(V)1.9 channels with a particularly low half maximal inhibitory concentration(IC50)for Na_(V)1.9 by promoting sodium channel inactivation,and also effectively increased K_(V)7.2/7.3,K_(V)7.2,and K_(V)7.5 channels,excluding K_(V)7.1 by promoting potassium channel activation.This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses,indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically.The safety of E0199 was supported by neurobehavioral evaluations.Conclusively,E0199 represents a ground-breaking approach in NP treatment,showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP.This study introduces a promising direction for the future development of NP therapeutics.
基金supported by the grants from National Natural Science Foundation of China(No. 30600173,81070893)the Key Project of China Ministry of Education(No. 109003)+1 种基金the National Basic Research Development Program(973 Program) of China (No.2007CB512501)Beijing Municipal Commission of Education "Special Grants for Outstanding Ph.D Program Tutors"
文摘Objective The present study aimed to investigate the electrophysiological properties of wide dynamic range （WDR） neurons in spinal dorsal horn of rats with neuropathic pain induced by lumber 5 （L5） spinal nerve ligation （SNL） in a large size of samples.Methods Adult Sprague-Dawley rats were divided into normal and SNL groups.Electrophysiological technique was used to record the characteristics of WDR neurons in the spinal dorsal horn.Results Compared with the WDR neurons in normal rats,the WDR neurons in SNL rats showed an increase in excitability,manifested by an enlargement of the receptive field size,an increase in the proportion of neurons that exhibited spontaneous activities,decreases in the Cresponse threshold and latency,and an increase in the C-response duration.In addition,the numbers of A-and C-fiberevoked discharges were smaller in SNL rats than in normal rats.Conclusion The excitability of spinal WDR neurons increased in rats with neuropathic pain induced by L5 SNL.The increase in excitability of WDR neurons may contribute to the development of neuropathic pain.
基金supported by the Project of Ministry of Health(Comprehensive Research on Brachial Plexus Injury),No.13D22270800 from the National Natural Science Foundation of China2011 Shanghai Medical College Young Scientist Fund of Fudan University,No.11L-24
文摘Electroacupuncture has traditionally been used to treat pain, but its effect on pain following brachial plexus injury is still unknown. In this study, rat models of an avulsion injury to the left brachial plexus root （associated with upper-limb chronic neuropathic pain） were given electroacupuncture stimulation at bilateral Quchi （LIll）, Hegu （LI04）, Zusanli （ST36） and Yanglingquan （GB34）. After electroacupuncture therapy, chronic neuropathic pain in the rats＇ upper limbs was significantly attenuated. Immunofluorescence staining showed that the expression of β-endorphins in the arcuate nucleus was significantly increased after therapy. Thus, experimental findings indi- cate that electroacupuncture can attenuate neuropathic pain after brachial plexus injury through upregulating β-endorphin expression.
基金supported by the National Natural Science Foundation of China(Nos.81570735,8181101216,31560276,81970749,and 81870574)
文摘Neuropathic pain(NP)has become a serious global health issue and a huge clinical challenge without available effective treatment.P2 receptors family is involved in pain transmission and represents a promising target for pharmacological intervention.Traditional Chinese medicine(TCM)contains multiple components which are effective in targeting different pathological mechanisms involved in NP.Different from traditional analgesics,which target a single pathway,TCMs take the advantage of multiple components and multiple targets,and can significantly improve the efficacy of treatment and contribute to the prediction of the risks of NP.Compounds of TCM acting at nucleotide P2 receptors in neurons and glial cells could be considered as a potential research direction for moderating neuropathic pain.This review summarized the recently published data and highlighted several TCMs that relieved NP by acting at P2 receptors.
文摘Diabetic neuropathy is a common complication of both type 1 and type 2 diabetes,which affects over 90% of the diabetic patients.Although pain is one of the main symptoms of diabetic neuropathy,its pathophysiological mechanisms are not yet fully known.It is widely accepted that the toxic effects of hyperglycemia play an important role in the development of this complication,but several other hypotheses have been postulated.The management of diabetic neuropathic pain consists basically in excluding other causes of painful peripheral neuropathy,improving glycemic control as a prophylactic therapy and using medications to alleviate pain.First line drugs for pain relief include anticonvulsants,such as pregabalin and gabapentin and antidepressants,especial y those that act to inhibit the reuptake of serotonin and noradrenaline.In addition,there is experimental and clinical evidence that opioids can be helpful in pain control,mainly if associated with first line drugs.Other agents,including for topical application,such as capsaicin cream and lidocaine patches,have also been proposed to be useful as adjuvants in the control of diabetic neuropathic pain,but the clinical evidence is insufficient to support their use.In conclusion,a better understanding of the mechanisms underlying diabetic neuropathic pain will contribute to the search of new therapies,but also to the improvement of the guidelines to optimize pain control with the drugs currently available.
基金supported by grants from the National Natural Science Foundation of China(31171070,81171060,81501070and 81571079)
文摘Emerging evidence indicates that CXCL12/ CXCR4 signaling is involved in chronic pain. However, few studies have systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mech- anism. Here, we determined that spared nerve injury （SNI） increased the expression of CXCL12 and its cognate receptor CXCR4 in lumbar 5 dorsal root ganglia （DRG） neurons and satellite glial cells. SNI also induced long- lasting upregulation of CXCL12 and CXCR4 in the ipsi- lateral L4-5 spinal cord dorsal horn, characterized by CXCL12 expression in neurons and microglia, and CXCR4 expression in neurons and astrocytes. Moreover, SNI- induced a sustained increase in TNF-α expression in the DRG and spinal cord. Intraperitoneal injection （i.p.） of the TNF-α synthesis inhibitor thalidomide reduced the SNI-in- duced mechanical hypersensitivity and inhibited the expression of CXCL12 in the DRG and spinal cord. Intrathecal injection （i.t.） of the CXCR4 antagonist AMD3100, both 30 rain before and 7 days after SNI, reduced the behavioral signs of allodynia. Rats given an i.t. or i.p. bolus of AMD3100 on day 8 of SNI exhibited attenuated abnormal pain behaviors. The neuropathic pain established following SNI was also impaired by i.t. admin- istration of a CXCL12-neutralizing antibody. Moreover, repetitive i.t. AMD3100 administration prevented the acti- vation of ERK in the spinal cord. The mechanical hyper- sensitivity induced in nai＇ve rats by i.t. CXCL12 was alleviated by pretreatment with the MEK inhibitor PD98059. Collectively, our results revealed that TNF-α might mediate the upregulation of CXCL12 in the DRG and spinal cord following SNI, and that CXCL 12/CXCR4 sig- naling via ERK activation contributes to the development and maintenance of neuropathic pain.
基金supported by grants from the National Natural Science Foundation of China (31671091 and 81771197)the Natural Science Foundation of Jiangsu Province, China (BK20171255)the Science and Technology Planning Project of Nantong Municipality, China (MS12017023-9)
文摘Pain consists of sensory-discriminative and emotional-affective components.The anterior cingulate cortex(ACC)is a critical brain area in mediating the affective pain.However,the molecular mechanisms involved remain largely unknown.Our recent study indicated that C-X-C motif chemokine 13(CXCL13)and its sole receptor CXCR5 are involved in sensory sensitization in the spinal cord after spinal nerve ligation(SNL).Whether CXCL13/CXCR5 signaling in the ACC contributes to the pathogenesis of pain-related aversion remains unknown.Here,we showed that SNL increased the CXCL13 level and CXCR5 expression in the ACC after SNL.Knockdown of CXCR5 by microinjection of Cxcr5 shRNA into the ACC did not affect SNL-induced mechanical allodynia but effectively alleviated neuropathic painrelated place avoidance behavior.Furthermore,electrophysiological recording from layer Ⅱ-Ⅲ neurons in the ACC showed that SNL increased the frequency and amplitude of spontaneous excitatory postsynaptic currents(sEPSCs),decreased the EPSC paired-pulse ratio,and increased the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor ratio,indicating enhanced glutamatergic synaptic transmission.Finally,superfusion of CXCL13 onto ACC slices increased the frequency and amplitude of spontaneous EPSCs.Pre-injection of Cxcr5 shRNA into the ACC reduced the increase in glutamatergic synaptic transmis sion induced by SNL.Collectively,these results suggest that CXCL13/CXCR5 signaling in the ACC is involved in neuropathic pain-related aversion via synaptic potentiation.
