Objective Magnetoencephalography(MEG),a non-invasive neuroimaging technique,meticulously captures the magnetic fields emanating from brain electrical activity.Compared with MEG based on superconducting quantum interfe...Objective Magnetoencephalography(MEG),a non-invasive neuroimaging technique,meticulously captures the magnetic fields emanating from brain electrical activity.Compared with MEG based on superconducting quantum interference devices(SQUID),MEG based on optically pump magnetometer(OPM)has the advantages of higher sensitivity,better spatial resolution and lower cost.However,most of the current studies are clinical studies,and there is a lack of animal studies on MEG based on OPM technology.Pain,a multifaceted sensory and emotional phenomenon,induces intricate alterations in brain activity,exhibiting notable sex differences.Despite clinical revelations of pain-related neuronal activity through MEG,specific properties remain elusive,and comprehensive laboratory studies on pain-associated brain activity alterations are lacking.The aim of this study was to investigate the effects of inflammatory pain(induced by Complete Freund’s Adjuvant(CFA))on brain activity in a rat model using the MEG technique,to analysis changes in brain activity during pain perception,and to explore sex differences in pain-related MEG signaling.Methods This study utilized adult male and female Sprague-Dawley rats.Inflammatory pain was induced via intraplantar injection of CFA(100μl,50%in saline)in the left hind paw,with control groups receiving saline.Pain behavior was assessed using von Frey filaments at baseline and 1 h post-injection.For MEG recording,anesthetized rats had an OPM positioned on their head within a magnetic shield,undergoing two 15-minute sessions:a 5-minute baseline followed by a 10-minute mechanical stimulation phase.Data analysis included artifact removal and time-frequency analysis of spontaneous brain activity using accumulated spectrograms,generating spectrograms focused on the 4-30 Hz frequency range.Results MEG recordings in anesthetized rats during resting states and hind paw mechanical stimulation were compared,before and after saline/CFA injections.Mechanical stimulation elevated alpha activity in both male and female rats pre-and post-saline/CFA injections.Saline/CFA injections augmented average power in both sexes compared to pre-injection states.Remarkably,female rats exhibited higher average spectral power 1 h after CFA injection than after saline injection during resting states.Furthermore,despite comparable pain thresholds measured by classical pain behavioral tests post-CFA treatment,female rats displayed higher average power than males in the resting state after CFA injection.Conclusion These results imply an enhanced perception of inflammatory pain in female rats compared to their male counterparts.Our study exhibits sex differences in alpha activities following CFA injection,highlighting heightened brain alpha activity in female rats during acute inflammatory pain in the resting state.Our study provides a method for OPM-based MEG recordings to be used to study brain activity in anaesthetized animals.In addition,the findings of this study contribute to a deeper understanding of pain-related neural activity and pain sex differences.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
Pain is a signal of inflammation that can have both protective and pathogenic effects.Macrophages,significant components of the immune system,play crucial roles in the occurrence and development of pain,particularly i...Pain is a signal of inflammation that can have both protective and pathogenic effects.Macrophages,significant components of the immune system,play crucial roles in the occurrence and development of pain,particularly in neuroimmune communication.Macrophages exhibit plasticity and heterogeneity,adopting either pro-inflammatory M1 or anti-inflammatory M2 phenotypes depending on their functional orientation.Recent research highlights the contribution of macrophages to pain dynamics by undergoing changes in their functional polarity,leading to macrophage activation,tissue infiltration,and cytokine secretion.M1 macrophages release pro-inflammatory mediators that are not only essential in defending against infections,but also contributing to tissue damage and the elicitation of pain.However,this process can be counteracted by M2 macrophages,facilitating pain relief through producing anti-inflammatory cytokines and opioid peptides or enhancing efferocytosis.M1 and M2 macrophages play important roles in both the initiation and mitigation of pain.展开更多
OBJECTIVE To investigate effects of oxymatrine,an alkaloid from Sophora flavescens Ait.,on high-voltage dependent calcium channel and inhibitory neurotransmitter GABA under neuropathic pain condition.METHODS The parti...OBJECTIVE To investigate effects of oxymatrine,an alkaloid from Sophora flavescens Ait.,on high-voltage dependent calcium channel and inhibitory neurotransmitter GABA under neuropathic pain condition.METHODS The partial sciatic nerve ligation(PSNL)was executed on C57/BL6 mice to produce neuropathic pain.Oxymatrine(150 mg·kg-1)was administrated intraperitoneally to PSNL mice.Mechanical hindpaw withdral threshold(MWT)was measured under Von-Frey filament stimulation with up-and-down method.In brain tissue,GABA concentration was measured with ELISA.Change of GABAAreceptor protein expression,N-type calcium channel(Cav2.2)and L-type calcium channel(Cav1.3)protein expressions were detected with Western-blot;intracellular calcium concentration was measured in cultured cortical neurons with Fluo-3/AM fluorescent probe.RESULTS Compared to saline,oxymatrine significantly increased ED50 of MWT on PSNL mice(P<0.05).GABA concentration and GABAAreceptor protein level in brain tissue were decreased in PSNL mice,while administration of oxymatrine increased both GABA concentration and GABAA receptor expression.Intracellular calcium concentration was increased in cultured cortical neurons by oxymatrine treatment,but this phenomenon was not seen under calcium-free condition.Protein expression of Cav2.2,but not Cav1.3,was found to be decreased in the brains of PSNL mice and to be restored to a normal level with oxymatrine administration.CONCLUSION Oxymatrine has analgesic effect on PSNL-induced neuropathic pain in mice.This phenominon relates to the increase of GABA release,GABAAreceptor expression,and also the restoration of expression level of Cav2.2 but not Cav1.3 in brain tissues,which suggesting that Ca2+ flow through Cav2.2 calcium channel may be the key point underlying oxymatrine analgesia.展开更多
Objective · Formalin is a classic and most widely used algogenic substance, but its itchy effect is not clear. The present study aims to explore the hypothesis that formalin may induce itch as well as pain. Metho...Objective · Formalin is a classic and most widely used algogenic substance, but its itchy effect is not clear. The present study aims to explore the hypothesis that formalin may induce itch as well as pain. Methods · Flinching, as well as licking and forelimb wiping of the site of injection were counted as pain responses, whereas biting and hind paw scratching of the cheek were counted as itchy responses. To discriminate formalin-induced sensations in rats, the irritant(saline as control) was injected, and then pain and itchy responses were recorded.Results · Intraplantar injection of formalin elicited biphasic behavior responses characterized as flinching, as well as biting or licking of the hind paw without significant gender differences. Following intradermal administration of formalin to the cheek, rats exhibited episodic forelimb wiping of the cheek, representative of pain. No gender difference was noticed for this type of behavior. In addition, episodes of hind paw scratches of the cheek, representative of pruritoceptive responses, also occurred. Interestingly, hind paw scratches appeared to be more pronounced in male than in female rats. Conclusion · Intradermal administration of formalin elicits pruritoceptive as well as nociceptive responses in rats.展开更多
Intense inflammatory pain caused by urate crystals in joints and other tissues is a major symptom of gout.Among therapy drugs that lower urate,benzbromarone(BBR),an inhibitor of urate transporters,is widely used becau...Intense inflammatory pain caused by urate crystals in joints and other tissues is a major symptom of gout.Among therapy drugs that lower urate,benzbromarone(BBR),an inhibitor of urate transporters,is widely used because it is well tolerated and highly effective.We demonstrate that BBR is also an activator of voltage-gated KCNQ potassium channels.In cultured recombinant cells,BBR exhibited significant potentiation effects on KCNQ channels comparable to previously reported classical activators.In native dorsal root ganglion neurons,BBR effectively overcame the suppression of KCNQ currents,and the resultant neuronal hyperexcitability caused by inflammatory mediators,such as bradykinin(BK).Benzbromarone consistently attenuates BK-,formalin-,or monosodium urate-induced inflammatory pain in rat and mouse models.Notably,the analgesic effects of BBR are largely mediated through peripheral and not through central KCNQ channels,an observation supported both by pharmacokinetic studies and in vivo experiments.Moreover,multiple residues in the superficial part of the voltage sensing domain of KCNQ channels were identified critical for the potentiation activity of BBR by a molecular determinant investigation.Our data indicate that activation of peripheral KCNQ channels mediates the pain relief effects of BBR,potentially providing a new strategy for the development of more effective therapies for gout.展开更多
OBJECTIVE To investigated the effects of INI-0602 on nociceptive reflex,depression-associated andanxiety-related behaviors caused by neuropathic pain in sciatic nerve injury rats.METHODS Male rat were subjected to sci...OBJECTIVE To investigated the effects of INI-0602 on nociceptive reflex,depression-associated andanxiety-related behaviors caused by neuropathic pain in sciatic nerve injury rats.METHODS Male rat were subjected to sciatic nerve injury(SNI)or sham surgery.Rat received daily treatment with INI-0602 intrathecally,at a dose of 0.25μg/10μL.The response frequency to mechanical allodynia in animals was measured with von Frey hairs on day 1,3,5,7,14,21.Rats were evaluated in the forced swimming test(FST)test,tail suspension test(TST),sucrose preference test(SPT)for depression-like behavior.We performed open field test(OFT)and elevated plus-maze test(EPM)to evaluate anxiety-associated behaviors.Besides,we investigated the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF)and also the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.RESULTS The SNI procedure produced mechanical allodynia and accompanied with depressive-like and anxiety-like behavior.Treatment with INI-0602 produced a significant analgesic effect in SNI rats at day 7(model+NS:11.017±1.506 g;model+INI-0602:31.157±1.532 g,P<0.01),and still obviously on the 21th day(31.067±1.787,P<0.01).INI-0602 could also improve the performance of sciatic nerve injury rats among program behavior tests related to depression and anxiety.In parallel with relief of pain,the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF),involved in central sensitization and synaptic plasticity,were investigated.INI-0602 not only could inhibited spared nerve injury induced up-regulated of NR2B and phosphorylation NR2B in early and late neuropathic pain(early phase:Nr2b:2.897±0.228,P<0.01;p-Nr2b:2.984±0.236,P<0.01;late phase:Nr2b:2.594±0.187,P<0.01;p-Nr2b:3.124±0.330,P<0.01),but also could inhibit the increased of BDNF in the early(model+NS:3.637±0.381,model+INI-0602:1.148±0.372,P<0.01)and upregulate the BDNF in late stage(model+NS:0.438±0.103,model+INI-0602:1.222±0.092,P<0.01).Meanwhile,INI-0602 significantly decreased the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.CONCLUSION INI-0602 blocked behavioral changes induced by neuropathic pain,suggesting that it might be a promising pharmacological approach of painemotion diseases.展开更多
This paper addresses the topic of an interdisciplinary approach of chronic pain management from a biopsychosocial perspective. The first section provides an introduction to the definitions and theories of chronic pain...This paper addresses the topic of an interdisciplinary approach of chronic pain management from a biopsychosocial perspective. The first section provides an introduction to the definitions and theories of chronic pain and the various contributing factors (psychological, interpersonal/environmental and social support, and vocational). The second section presents the role of various health care professions (medical doctors, nurses, physical therapists, occupational therapists, psychologists and rehabilitation counselors) and the evidence of their treatment effectiveness. The third section discusses the concept of an interdisciplinary pain rehabilitation program (IPRP) and its evidence to support its effectiveness. Finally, the clinical implications of rehabilitation counseling and psychology as part of the inter-disciplinary program in treating individuals with chronic pain will be highlighted.展开更多
Objective:To compare the balance ability between normal people and non-specific low back pain(nsLBP) patients and explore the relationship between balance ability and muscle function in nsLBP patients.Method:Ten nsLBP...Objective:To compare the balance ability between normal people and non-specific low back pain(nsLBP) patients and explore the relationship between balance ability and muscle function in nsLBP patients.Method:Ten nsLBP patients as nsLBP group and 10 age and gender-matched healthy control subjects as control group were investigated.Posturography on balance platform and surface electromyography(sEMG) were performed to assess all the subjects' function of equilibrium and muscle activities of erector spinea(ES),multifidus(MF),abdominal external oblique(EO),hamstring(HS) and maximal gluteus(MG) bilaterally.Result:The nsLBP subjects had greater sway on anterior-posterior direction(Y-speed and Y-extension,P=0.05) on feet-together posture and bigger main axis(P=0.023) on nature standing with eyes closed when compared with controls.The iEMG ratios of right MG in nature standing(eyes closed)/nature standing(eyes open) and feet-together(eyes open)/nature standing(eyes open) in control group were significant higher than that in nsLBP group(P=0.03 and P=0.013).Conclusion:Balance evaluation combined with sEMG measurement on trank and lower limb muscles provided some quantitative information about functional deficits such as postural control and muscle activities in nsLBP patients.This relationship should be emphasized in prevention and rehabilitation of nsLBP.展开更多
Glycation of nucleotides, proteins and phospholipids contributes to the development of late diabetic complications,including the most debilitating one——diabetic neuropathy. Reactive intermediates of AGE formation su...Glycation of nucleotides, proteins and phospholipids contributes to the development of late diabetic complications,including the most debilitating one——diabetic neuropathy. Reactive intermediates of AGE formation such as glyoxal, methylglyoxal(MG) and other dicarbonyls are detoxified by the glyoxalase-system. However little is known about the regulation and nature of the mechanisms underlying neuropathology. Therefore we decided to focus on the role of MG-glyoxalase 1(GLO-1) system in modulation of painful diabetic neuropathy.展开更多
OBJECTIVE The present study was aimed to investigate the role of Wnt/β-catenin sig.naling in spinal VGLUT2 regulation and neuropathic pain.METHODS To elucidate the association be.tween VGLUT2 and neuropathic pain,we ...OBJECTIVE The present study was aimed to investigate the role of Wnt/β-catenin sig.naling in spinal VGLUT2 regulation and neuropathic pain.METHODS To elucidate the association be.tween VGLUT2 and neuropathic pain,we determined the expression and distribution characteristics of VGLUT2 in mice subjected to spared nerve injury(SNI),and then observed the effects of two VGLUT2 targeting shRNAs on mechanical allodynia and glutamate release.The effects of Wnt/β-catenin signal.ing on VGLUT2 expression and pain behavior were investigated by using Wnt agonist,Wnt1,and Wnt/β-catenin pathway inhibitor XAV939 in SNI mice.RESULTS SNI surgery induced significant up-regula.tion of VGLUT2 on postoperative days 7,14,and 21.Double immunofluorescence labeling of VGLUT2 with NeuN,MAP2,Iba-1,or GFAP showed that VGLUT2 was mainly expressed in neurons in the dor.sal horn of the spinal cord after SNI(NeuN,MAP2).Intrathecal administration of VGLUT2 shRNAs be.fore or after SNI surgery significantly decreased mechanical allodynia and glutamate release.Mean.while,Wnt1/β-catenin signaling increased significantly after SNI surgery.Over-expression of β-catenin in PC12 cells increased VGLUT2 protein level,intrathecal administration of Wnt agonist or Wnt1 signifi.cantly increased VGLUT2 protein expression in spinal cord,while Wnt/β-catenin pathway inhibitor XAV939 decreased VGLUT2 expression in PC12 cells and spinal cord.Additionally,intrathecal admin.istration of XAV939 7 days after SNI significantly attenuated mechanical allodynia in mice,which was in accordance with down-regulation of VGLUT2 protein levels.VGLUT2 shRNAs significantly attenuat.ed Wnt agonist or Wnt1 induced mechanical allodynia.CONCLUSION Wnt1/β-catenin signaling path.way up-regu-lates the spinal VGLUT2 expression,and this regulation is involved in neuropathic pain behavior.展开更多
Introduction:Patients with pain contribute to 60%-70% of emergency department(ED)attendance and the tramadol is among analgesic of choice in ED.However,the use of intravenous tramadol is limited to moderate pain inten...Introduction:Patients with pain contribute to 60%-70% of emergency department(ED)attendance and the tramadol is among analgesic of choice in ED.However,the use of intravenous tramadol is limited to moderate pain intensity because of its weak opiod agonist properties.We conducted a study to examine the effectiveness of intravenous tramadol among patients who suffer from severe traumatic pain.Methodology:In this prospective study,eligible patients received a loading dose of intravenous tramadol(2mg/kg).If visual analogue score(VAS)more than 30 mm after the loading dose,intermittent bolus intravenous tramadol 20mg will be administered every 10 minutes.At 30 minutes of study,rescue medication(i.e.morphine or pethidine)will be provided to those patients with VAS more than 30 mm.VAS score,vital signs and side effects were recorded for every 10 minutesResults:Forty-seven patients who suffered from fracture and soft tissue injury were analysed.The median VAS score on presentation and at 30 minutes was 90 mm 20 mm respectively.The median total dose of IV tramadol received by the patients at 30 minutes was 150 mg(IQR=34.0).There was a significant change in medium pain score at 10,20 and 30 minutes treatment(P<0.001).Vital signs were within normal range throughout the study period.About 66.1% of them had side effects of tramadol.The common side effects were sleepiness(75.0%)and dizziness(56.3%).Conclusion:The intravenous tramadol is a safe and effective analgesia in severe traumatic patients if an initial and intermittent dose is given adequately.展开更多
Bone metastasis occurs as a result of a complex pathophysiologic process between host and tumor cells leading tO cellular invasion,migration adhesion,and stimulation of osteoclastic and osteoblastic activity.Several s...Bone metastasis occurs as a result of a complex pathophysiologic process between host and tumor cells leading tO cellular invasion,migration adhesion,and stimulation of osteoclastic and osteoblastic activity.Several sequences occur as a result of osseous metastases and resulting bone pain Can lead to significant debilitation.Pain associated with osseous metastasis is thought to be distinct from neuropathic or inflammatory pain.Several mechanisms,such as invasion of tumor cells,spinal cord astrogliosis. and sensitization of nervous system,have been postulated to cause pain.Pharmaceutical therapy of bone pain includes nonsteroidal analgesics and opiates.These drugs are associated with side effects,and tolerance to these agents necessitates treatment with other modalities.Bisphosphonates act by inhibiting osteoclast—mediated resorption and have been increasingly used in treatment of pain- ful bone metastasis.While external beam radiation therapy remains the mainstay of pain palliation of solitary lesions,bone-seeking radiopharmaceuticals have entered the therapeutic armamentarium for the treatment of multiple painful osseous lesions.32P has been used for over 3 decades in the treatment of multiple osseous metastases.The myelosuppression caused by this agent has led to the development of other bone-seeking radiopharmaceuticals.including 89SrCl.and 153Sm-ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP).89Sr is a bone-seeking radionuclide.whereas 153Sm—EDTMP is a bone—seeking tetraphosphonate;both have been approved by the Food and Drug Administration for the treatment of painful osseous metastases.While both agents have been shown to have efficacy in the treatment of painful osseous metastases from prostate cancer,they may also have utility in the treatment of painful OSSEOUS metastases from breast cancer and perhaps from non—small cell lung cancer.This article illustrates the salient features of these radiopharmaceuticals,including the approved dose,method of administration,and indications for use.展开更多
文摘Objective Magnetoencephalography(MEG),a non-invasive neuroimaging technique,meticulously captures the magnetic fields emanating from brain electrical activity.Compared with MEG based on superconducting quantum interference devices(SQUID),MEG based on optically pump magnetometer(OPM)has the advantages of higher sensitivity,better spatial resolution and lower cost.However,most of the current studies are clinical studies,and there is a lack of animal studies on MEG based on OPM technology.Pain,a multifaceted sensory and emotional phenomenon,induces intricate alterations in brain activity,exhibiting notable sex differences.Despite clinical revelations of pain-related neuronal activity through MEG,specific properties remain elusive,and comprehensive laboratory studies on pain-associated brain activity alterations are lacking.The aim of this study was to investigate the effects of inflammatory pain(induced by Complete Freund’s Adjuvant(CFA))on brain activity in a rat model using the MEG technique,to analysis changes in brain activity during pain perception,and to explore sex differences in pain-related MEG signaling.Methods This study utilized adult male and female Sprague-Dawley rats.Inflammatory pain was induced via intraplantar injection of CFA(100μl,50%in saline)in the left hind paw,with control groups receiving saline.Pain behavior was assessed using von Frey filaments at baseline and 1 h post-injection.For MEG recording,anesthetized rats had an OPM positioned on their head within a magnetic shield,undergoing two 15-minute sessions:a 5-minute baseline followed by a 10-minute mechanical stimulation phase.Data analysis included artifact removal and time-frequency analysis of spontaneous brain activity using accumulated spectrograms,generating spectrograms focused on the 4-30 Hz frequency range.Results MEG recordings in anesthetized rats during resting states and hind paw mechanical stimulation were compared,before and after saline/CFA injections.Mechanical stimulation elevated alpha activity in both male and female rats pre-and post-saline/CFA injections.Saline/CFA injections augmented average power in both sexes compared to pre-injection states.Remarkably,female rats exhibited higher average spectral power 1 h after CFA injection than after saline injection during resting states.Furthermore,despite comparable pain thresholds measured by classical pain behavioral tests post-CFA treatment,female rats displayed higher average power than males in the resting state after CFA injection.Conclusion These results imply an enhanced perception of inflammatory pain in female rats compared to their male counterparts.Our study exhibits sex differences in alpha activities following CFA injection,highlighting heightened brain alpha activity in female rats during acute inflammatory pain in the resting state.Our study provides a method for OPM-based MEG recordings to be used to study brain activity in anaesthetized animals.In addition,the findings of this study contribute to a deeper understanding of pain-related neural activity and pain sex differences.
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.
基金supported by the Natural Science Foundation of Hunan Province(2021JJ41060,2022JJ30972)the Changsha Municipal Natural Science Foundation(kq2014280)+1 种基金the Research Program Project of Hunan Health Commission(B202304119634)China。
文摘Pain is a signal of inflammation that can have both protective and pathogenic effects.Macrophages,significant components of the immune system,play crucial roles in the occurrence and development of pain,particularly in neuroimmune communication.Macrophages exhibit plasticity and heterogeneity,adopting either pro-inflammatory M1 or anti-inflammatory M2 phenotypes depending on their functional orientation.Recent research highlights the contribution of macrophages to pain dynamics by undergoing changes in their functional polarity,leading to macrophage activation,tissue infiltration,and cytokine secretion.M1 macrophages release pro-inflammatory mediators that are not only essential in defending against infections,but also contributing to tissue damage and the elicitation of pain.However,this process can be counteracted by M2 macrophages,facilitating pain relief through producing anti-inflammatory cytokines and opioid peptides or enhancing efferocytosis.M1 and M2 macrophages play important roles in both the initiation and mitigation of pain.
基金The project supported by National Natural Science Foundation of China(81102901)Scientific Research Foundation for Returned Chinese Scholars([2012]940)Natural Science Foundation of Liaoning Province(201102151)
文摘OBJECTIVE To investigate effects of oxymatrine,an alkaloid from Sophora flavescens Ait.,on high-voltage dependent calcium channel and inhibitory neurotransmitter GABA under neuropathic pain condition.METHODS The partial sciatic nerve ligation(PSNL)was executed on C57/BL6 mice to produce neuropathic pain.Oxymatrine(150 mg·kg-1)was administrated intraperitoneally to PSNL mice.Mechanical hindpaw withdral threshold(MWT)was measured under Von-Frey filament stimulation with up-and-down method.In brain tissue,GABA concentration was measured with ELISA.Change of GABAAreceptor protein expression,N-type calcium channel(Cav2.2)and L-type calcium channel(Cav1.3)protein expressions were detected with Western-blot;intracellular calcium concentration was measured in cultured cortical neurons with Fluo-3/AM fluorescent probe.RESULTS Compared to saline,oxymatrine significantly increased ED50 of MWT on PSNL mice(P<0.05).GABA concentration and GABAAreceptor protein level in brain tissue were decreased in PSNL mice,while administration of oxymatrine increased both GABA concentration and GABAA receptor expression.Intracellular calcium concentration was increased in cultured cortical neurons by oxymatrine treatment,but this phenomenon was not seen under calcium-free condition.Protein expression of Cav2.2,but not Cav1.3,was found to be decreased in the brains of PSNL mice and to be restored to a normal level with oxymatrine administration.CONCLUSION Oxymatrine has analgesic effect on PSNL-induced neuropathic pain in mice.This phenominon relates to the increase of GABA release,GABAAreceptor expression,and also the restoration of expression level of Cav2.2 but not Cav1.3 in brain tissues,which suggesting that Ca2+ flow through Cav2.2 calcium channel may be the key point underlying oxymatrine analgesia.
文摘Objective · Formalin is a classic and most widely used algogenic substance, but its itchy effect is not clear. The present study aims to explore the hypothesis that formalin may induce itch as well as pain. Methods · Flinching, as well as licking and forelimb wiping of the site of injection were counted as pain responses, whereas biting and hind paw scratching of the cheek were counted as itchy responses. To discriminate formalin-induced sensations in rats, the irritant(saline as control) was injected, and then pain and itchy responses were recorded.Results · Intraplantar injection of formalin elicited biphasic behavior responses characterized as flinching, as well as biting or licking of the hind paw without significant gender differences. Following intradermal administration of formalin to the cheek, rats exhibited episodic forelimb wiping of the cheek, representative of pain. No gender difference was noticed for this type of behavior. In addition, episodes of hind paw scratches of the cheek, representative of pruritoceptive responses, also occurred. Interestingly, hind paw scratches appeared to be more pronounced in male than in female rats. Conclusion · Intradermal administration of formalin elicits pruritoceptive as well as nociceptive responses in rats.
文摘Intense inflammatory pain caused by urate crystals in joints and other tissues is a major symptom of gout.Among therapy drugs that lower urate,benzbromarone(BBR),an inhibitor of urate transporters,is widely used because it is well tolerated and highly effective.We demonstrate that BBR is also an activator of voltage-gated KCNQ potassium channels.In cultured recombinant cells,BBR exhibited significant potentiation effects on KCNQ channels comparable to previously reported classical activators.In native dorsal root ganglion neurons,BBR effectively overcame the suppression of KCNQ currents,and the resultant neuronal hyperexcitability caused by inflammatory mediators,such as bradykinin(BK).Benzbromarone consistently attenuates BK-,formalin-,or monosodium urate-induced inflammatory pain in rat and mouse models.Notably,the analgesic effects of BBR are largely mediated through peripheral and not through central KCNQ channels,an observation supported both by pharmacokinetic studies and in vivo experiments.Moreover,multiple residues in the superficial part of the voltage sensing domain of KCNQ channels were identified critical for the potentiation activity of BBR by a molecular determinant investigation.Our data indicate that activation of peripheral KCNQ channels mediates the pain relief effects of BBR,potentially providing a new strategy for the development of more effective therapies for gout.
基金The project supported by National Natural Science Foundation of China(81473234,U1303221)
文摘OBJECTIVE To investigated the effects of INI-0602 on nociceptive reflex,depression-associated andanxiety-related behaviors caused by neuropathic pain in sciatic nerve injury rats.METHODS Male rat were subjected to sciatic nerve injury(SNI)or sham surgery.Rat received daily treatment with INI-0602 intrathecally,at a dose of 0.25μg/10μL.The response frequency to mechanical allodynia in animals was measured with von Frey hairs on day 1,3,5,7,14,21.Rats were evaluated in the forced swimming test(FST)test,tail suspension test(TST),sucrose preference test(SPT)for depression-like behavior.We performed open field test(OFT)and elevated plus-maze test(EPM)to evaluate anxiety-associated behaviors.Besides,we investigated the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF)and also the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.RESULTS The SNI procedure produced mechanical allodynia and accompanied with depressive-like and anxiety-like behavior.Treatment with INI-0602 produced a significant analgesic effect in SNI rats at day 7(model+NS:11.017±1.506 g;model+INI-0602:31.157±1.532 g,P<0.01),and still obviously on the 21th day(31.067±1.787,P<0.01).INI-0602 could also improve the performance of sciatic nerve injury rats among program behavior tests related to depression and anxiety.In parallel with relief of pain,the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF),involved in central sensitization and synaptic plasticity,were investigated.INI-0602 not only could inhibited spared nerve injury induced up-regulated of NR2B and phosphorylation NR2B in early and late neuropathic pain(early phase:Nr2b:2.897±0.228,P<0.01;p-Nr2b:2.984±0.236,P<0.01;late phase:Nr2b:2.594±0.187,P<0.01;p-Nr2b:3.124±0.330,P<0.01),but also could inhibit the increased of BDNF in the early(model+NS:3.637±0.381,model+INI-0602:1.148±0.372,P<0.01)and upregulate the BDNF in late stage(model+NS:0.438±0.103,model+INI-0602:1.222±0.092,P<0.01).Meanwhile,INI-0602 significantly decreased the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.CONCLUSION INI-0602 blocked behavioral changes induced by neuropathic pain,suggesting that it might be a promising pharmacological approach of painemotion diseases.
文摘This paper addresses the topic of an interdisciplinary approach of chronic pain management from a biopsychosocial perspective. The first section provides an introduction to the definitions and theories of chronic pain and the various contributing factors (psychological, interpersonal/environmental and social support, and vocational). The second section presents the role of various health care professions (medical doctors, nurses, physical therapists, occupational therapists, psychologists and rehabilitation counselors) and the evidence of their treatment effectiveness. The third section discusses the concept of an interdisciplinary pain rehabilitation program (IPRP) and its evidence to support its effectiveness. Finally, the clinical implications of rehabilitation counseling and psychology as part of the inter-disciplinary program in treating individuals with chronic pain will be highlighted.
基金The Expert Workshop(Liverpool,UK,October 2012),upon which the present manuscript was based,was supported by The Pain Relief Foundation,Liverpool The Great-Britain Sasakawa Foundation Awards ProgrammeBaxter+3 种基金BPLBiotestCSLBehringand Grifols
基金Funding by Beijing Technique Committee(D08050700330000)
文摘Objective:To compare the balance ability between normal people and non-specific low back pain(nsLBP) patients and explore the relationship between balance ability and muscle function in nsLBP patients.Method:Ten nsLBP patients as nsLBP group and 10 age and gender-matched healthy control subjects as control group were investigated.Posturography on balance platform and surface electromyography(sEMG) were performed to assess all the subjects' function of equilibrium and muscle activities of erector spinea(ES),multifidus(MF),abdominal external oblique(EO),hamstring(HS) and maximal gluteus(MG) bilaterally.Result:The nsLBP subjects had greater sway on anterior-posterior direction(Y-speed and Y-extension,P=0.05) on feet-together posture and bigger main axis(P=0.023) on nature standing with eyes closed when compared with controls.The iEMG ratios of right MG in nature standing(eyes closed)/nature standing(eyes open) and feet-together(eyes open)/nature standing(eyes open) in control group were significant higher than that in nsLBP group(P=0.03 and P=0.013).Conclusion:Balance evaluation combined with sEMG measurement on trank and lower limb muscles provided some quantitative information about functional deficits such as postural control and muscle activities in nsLBP patients.This relationship should be emphasized in prevention and rehabilitation of nsLBP.
文摘Glycation of nucleotides, proteins and phospholipids contributes to the development of late diabetic complications,including the most debilitating one——diabetic neuropathy. Reactive intermediates of AGE formation such as glyoxal, methylglyoxal(MG) and other dicarbonyls are detoxified by the glyoxalase-system. However little is known about the regulation and nature of the mechanisms underlying neuropathology. Therefore we decided to focus on the role of MG-glyoxalase 1(GLO-1) system in modulation of painful diabetic neuropathy.
基金supported by National Natural Science Foundation of China(81200850) Beijing Natural Science Foundation(7123224) National Science and Technology Major Project of China(2012ZX09301003-001)
文摘OBJECTIVE The present study was aimed to investigate the role of Wnt/β-catenin sig.naling in spinal VGLUT2 regulation and neuropathic pain.METHODS To elucidate the association be.tween VGLUT2 and neuropathic pain,we determined the expression and distribution characteristics of VGLUT2 in mice subjected to spared nerve injury(SNI),and then observed the effects of two VGLUT2 targeting shRNAs on mechanical allodynia and glutamate release.The effects of Wnt/β-catenin signal.ing on VGLUT2 expression and pain behavior were investigated by using Wnt agonist,Wnt1,and Wnt/β-catenin pathway inhibitor XAV939 in SNI mice.RESULTS SNI surgery induced significant up-regula.tion of VGLUT2 on postoperative days 7,14,and 21.Double immunofluorescence labeling of VGLUT2 with NeuN,MAP2,Iba-1,or GFAP showed that VGLUT2 was mainly expressed in neurons in the dor.sal horn of the spinal cord after SNI(NeuN,MAP2).Intrathecal administration of VGLUT2 shRNAs be.fore or after SNI surgery significantly decreased mechanical allodynia and glutamate release.Mean.while,Wnt1/β-catenin signaling increased significantly after SNI surgery.Over-expression of β-catenin in PC12 cells increased VGLUT2 protein level,intrathecal administration of Wnt agonist or Wnt1 signifi.cantly increased VGLUT2 protein expression in spinal cord,while Wnt/β-catenin pathway inhibitor XAV939 decreased VGLUT2 expression in PC12 cells and spinal cord.Additionally,intrathecal admin.istration of XAV939 7 days after SNI significantly attenuated mechanical allodynia in mice,which was in accordance with down-regulation of VGLUT2 protein levels.VGLUT2 shRNAs significantly attenuat.ed Wnt agonist or Wnt1 induced mechanical allodynia.CONCLUSION Wnt1/β-catenin signaling path.way up-regu-lates the spinal VGLUT2 expression,and this regulation is involved in neuropathic pain behavior.
文摘Introduction:Patients with pain contribute to 60%-70% of emergency department(ED)attendance and the tramadol is among analgesic of choice in ED.However,the use of intravenous tramadol is limited to moderate pain intensity because of its weak opiod agonist properties.We conducted a study to examine the effectiveness of intravenous tramadol among patients who suffer from severe traumatic pain.Methodology:In this prospective study,eligible patients received a loading dose of intravenous tramadol(2mg/kg).If visual analogue score(VAS)more than 30 mm after the loading dose,intermittent bolus intravenous tramadol 20mg will be administered every 10 minutes.At 30 minutes of study,rescue medication(i.e.morphine or pethidine)will be provided to those patients with VAS more than 30 mm.VAS score,vital signs and side effects were recorded for every 10 minutesResults:Forty-seven patients who suffered from fracture and soft tissue injury were analysed.The median VAS score on presentation and at 30 minutes was 90 mm 20 mm respectively.The median total dose of IV tramadol received by the patients at 30 minutes was 150 mg(IQR=34.0).There was a significant change in medium pain score at 10,20 and 30 minutes treatment(P<0.001).Vital signs were within normal range throughout the study period.About 66.1% of them had side effects of tramadol.The common side effects were sleepiness(75.0%)and dizziness(56.3%).Conclusion:The intravenous tramadol is a safe and effective analgesia in severe traumatic patients if an initial and intermittent dose is given adequately.
文摘Bone metastasis occurs as a result of a complex pathophysiologic process between host and tumor cells leading tO cellular invasion,migration adhesion,and stimulation of osteoclastic and osteoblastic activity.Several sequences occur as a result of osseous metastases and resulting bone pain Can lead to significant debilitation.Pain associated with osseous metastasis is thought to be distinct from neuropathic or inflammatory pain.Several mechanisms,such as invasion of tumor cells,spinal cord astrogliosis. and sensitization of nervous system,have been postulated to cause pain.Pharmaceutical therapy of bone pain includes nonsteroidal analgesics and opiates.These drugs are associated with side effects,and tolerance to these agents necessitates treatment with other modalities.Bisphosphonates act by inhibiting osteoclast—mediated resorption and have been increasingly used in treatment of pain- ful bone metastasis.While external beam radiation therapy remains the mainstay of pain palliation of solitary lesions,bone-seeking radiopharmaceuticals have entered the therapeutic armamentarium for the treatment of multiple painful osseous lesions.32P has been used for over 3 decades in the treatment of multiple osseous metastases.The myelosuppression caused by this agent has led to the development of other bone-seeking radiopharmaceuticals.including 89SrCl.and 153Sm-ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP).89Sr is a bone-seeking radionuclide.whereas 153Sm—EDTMP is a bone—seeking tetraphosphonate;both have been approved by the Food and Drug Administration for the treatment of painful osseous metastases.While both agents have been shown to have efficacy in the treatment of painful osseous metastases from prostate cancer,they may also have utility in the treatment of painful OSSEOUS metastases from breast cancer and perhaps from non—small cell lung cancer.This article illustrates the salient features of these radiopharmaceuticals,including the approved dose,method of administration,and indications for use.
