Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.030
Filtrar
2.
Psychopharmacology (Berl) ; 238(3): 877-886, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33404738

RESUMO

BACKGROUND: Memory deficit is a common cognitive comorbid in patients with neuropathic pain that need better treatment. Recent research revealed that nanocurcumin has an antinociceptive action and a protective effect against memory disorders, suggesting its possible effectiveness for the treatment of neuropathic pain and its comorbidity. METHODS: Adult male albino Wistar rats (n = 32) were randomly divided into four experimental groups: CCI+ nanocurcumin, CCI + vehicle, sham + nanocurcumin, and sham + vehicle. Neuropathic pain induced by a chronic constriction injury of the sciatic nerve. Nanocurcumin or vehicle was injected intraperitoneally for 10 days. Behavioral assessment achieved to evaluate pain threshold in the von Frey test and radiant heat test, also spatial learning and memory examined by the Morris water maze (MWM) test. To explore the possible relation, IL-1ß, and TNF-α levels of the hippocampus measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our data showed that CCI caused neuropathic pain-related behaviors and spatial learning and memory disorders in rats. Chronic treatment with nanocurcumin significantly increased pain threshold (P < 0.001; F = 27.63, F = 20.58), improved spatial memory (P < 0.01; F = 47.37), and decreased the hippocampal levels of IL-1ß (P < 0.001; F = 33.57) and TNF-α (P < 0.01; F = 7.25) in CCI rats. CONCLUSION: Chronic nanocurcumin can ameliorate pain-related behavior, improve spatial learning and memory deficits, and is associated with the reduction of IL-1ß and TNF-α levels in the hippocampus in CCI rats. Nanocurcumin may be potentially providing a therapeutic alternative for the treatment of neuropathic pain and its memory impairment comorbidity.


Assuntos
Analgésicos/uso terapêutico , Curcumina/uso terapêutico , Hipocampo/efeitos dos fármacos , Interleucina-1beta/metabolismo , Neuralgia/tratamento farmacológico , Memória Espacial/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Comportamento Animal/efeitos dos fármacos , Constrição , Curcumina/administração & dosagem , Curcumina/química , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Transtornos da Memória/complicações , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Nanopartículas/administração & dosagem , Nanopartículas/química , Neuralgia/complicações , Neuralgia/metabolismo , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões
3.
Gene ; 767: 145079, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32860901

RESUMO

Neuropathic pain is a most challenging diseases worldwide, caused by the injury of nerve system. CircularRNAs (circRNAs) are revealed to be involved in various diseases, includingneuropathic pain. However, the waycircRNAsparticipate in the progress ofneuropathic painstill needs further study. Identifyingthe possible circRNAexpression patterns of neuropathic painis of great significance to understand its underlying mechanism. Previously, circ_0005075 has been regarded as an important oncogene in multiple cancers and it has been characterized as an inflammation­associated circRNA in various processes. Nevertheless, the functional role of circ_0005075 in neuropathic pain development is still poorly known. In our present study, we observed circ_0005075 was obviously increased in CCI rat models. Knockdown of circ_0005075 repressed thebehaviors of neuropathic pain including mechanical and thermal hyperalgesia. Moreover, loss of circ_0005075 could repress the neuroinflammation via targeting COX-2, IL-6 and TNF-α whereas inducing IL-10 in vivo. Additionally, we predicted miR-151a-3p as the potential target of circ_0005075 using bioinformatics analysis. We displayed that miR-151a-3p was greatly reduced in CCI rats and circ_0005075 reversed the repressive effect of miR-151a-3p on neuropathic pain. For another, NOTCH2 has been shown to induce a variety of intracellular responses correlated withneuropathic pain. Here, we found NOTCH2 expression was strongly induced in CCI rats and miR-151a-3p. In addition, circ_0005075 significantly rescued NOTCH2 expression, which could be repressed by miR-151a-3p. To sum up, we indicated that loss ofcirc_0005075relieved neuropathic pain progression by inducement of miR-151a-3p and inactivation of NOTCH2 signaling.


Assuntos
MicroRNAs/genética , Neuralgia/genética , RNA Circular/genética , Animais , Progressão da Doença , Inflamação/metabolismo , Interleucina-6/genética , Masculino , MicroRNAs/metabolismo , Neuralgia/metabolismo , RNA Longo não Codificante/genética , Ratos , Ratos Sprague-Dawley , Receptor Notch2/genética , Receptor Notch2/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética
4.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333849

RESUMO

Neuropathic pain is characterized by spontaneous pain, pain sensations, and tactile allodynia. The pain sensory system normally functions under a fine balance between excitation and inhibition. Neuropathic pain arises when this balance is lost for some reason. In past reports, various mechanisms of neuropathic pain development have been reported, one of which is the downregulation of K+-Cl--cotransporter-2 (KCC2) expression. In fact, various neuropathic pain models indicate a decrease in KCC2 expression. This decrease in KCC2 expression is often due to a brain-derived neurotrophic factor that is released from microglia. However, a similar reaction has been reported in astrocytes, and it is unclear whether astrocytes or microglia are more important. This review discusses the hypothesis that astrocytes have a crucial influence on the alteration of KCC2 expression.


Assuntos
Astrócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sistema Nervoso Central/metabolismo , Neuralgia/metabolismo , Transdução de Sinais/fisiologia , Simportadores/metabolismo , Animais , Astrócitos/enzimologia , Sistema Nervoso Central/lesões , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Metaloproteinases da Matriz/metabolismo , Neuralgia/enzimologia , Receptor trkB/metabolismo , Ferimentos e Lesões/enzimologia , Ferimentos e Lesões/metabolismo
5.
Pain Res Manag ; 2020: 8309745, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33381249

RESUMO

This study set out to investigate the effect of massage on the Toll-like receptor 4 (TLR4) signalling pathway in the dorsal root ganglia of rats that had undergone spinal nerve ligation (SNL), with the hypothesis that massage could be used as an analgesic. Forty female SD rats were randomly divided into 5 groups: the control group, sham-operated group, model group, sham massage group, and massage group. There were 8 rats in each group. SNL rat models were established in the model group, sham massage group, and massage group. Rats in the sham-operated group underwent surgery to expose the vertebral nerves, but no further procedures were performed. The control group consisted of intact animals. The rats in the massage group underwent massage using a massage simulation machine once a day for 14 d in succession; the hind limbs of the rats in the sham massage group were gently touched with a cloth bag once a day for 14 continuous days. The rats in the control group, the sham-operated group, and the model group did not receive any intervention and were observed for 14 d. Paw withdrawal thermal latency (PWTL) and paw withdrawal mechanical threshold (PWMT) of rats in each group were detected 1 d before modelling and at 1, 3, 7, and 14 d after modelling. Fourteen days after modelling, the expression levels of TLR4, IRAK1, TRAF6, TNF-α, and IL-6 were detected in all rats. The PWTL and PWMT of SNL rats were decreased, while these parameters were elevated after massage. SNL rats showed higher levels of TLR4, IRAK1, TRAF6, IL-6, and TNF-α, and massage effectively lowered the expression levels of these molecules. Inhibiting activation of the TLR4 signalling pathway, which can reduce the release of inflammatory factors, may be one mechanism by which massage treats neuropathic pain.


Assuntos
Massagem/métodos , Neuralgia/metabolismo , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismo , Animais , Feminino , Estimulação Física/métodos , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/lesões
6.
Gene ; 763: 145069, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32827683

RESUMO

Neuropathic pain is caused by damage or disease happened to somatosensory nerve system. Due to the high prevalence and inefficient clinic intervention, neuropathic pain has brought considerable burden for world health care system. It is urgent to find novel targets for neuropathic pain basic research and clinical management. In this study, we found that miR-22-3p was decreased in Chronic Constriction Injury (CCI)rats and involved in neuropathic pain progression. Furthermore, it was found that ENO1 was a downstream target of miR-22-3p using bioinformatics analysis and luciferase reporter assays. MiR-22-3p downregulation promoted neuropathic pain via regulating inflammation factors expression by targeting ENO1. Then, we explored the upstream regulator of miR-22-3p using Miranda database. It was found that circular RNA ZNF609 sponged miR-22-3p by biotinylated RNA pull-down, AGO2-RIP, and luciferase reporter assays. Collectively, our study revealed that circZNF609 promoted inflammation factors expression to aggravate neuropathic pain progression via miR-22-3p/ENO1 axis in CCI rat models. Our study might provide a new direction for neuropathic pain basic research.


Assuntos
MicroRNAs/metabolismo , Neuralgia/metabolismo , Fosfopiruvato Hidratase/genética , RNA Circular/metabolismo , Animais , Células Cultivadas , Células HEK293 , Humanos , Masculino , MicroRNAs/genética , Neuralgia/genética , Fosfopiruvato Hidratase/metabolismo , RNA Circular/genética , Ratos , Ratos Sprague-Dawley
7.
Phytomedicine ; 78: 153307, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32846405

RESUMO

BACKGROUND: Current therapies for neuropathic pain are generally symptomatic and possess several side effects, limiting their prolonged usage. HYPOTHESIS/PURPOSE: Thus, it is urgent to develop novel and safe candidates for the management of this chronical condition. For this purpose, we investigated the analgesic effect of a standardized extract from Zingiber officinale Roscoe rhizomes (ZOE) obtained by CO2 supercritical extraction, in a mice model of peripheral neuropathy. We also explored the mechanism of action of ZOE and its main constituents using an in vitro model of neuroinflammation. METHODS: Peripheral mono-neuropathy was induced in mice, by spared nerve injury (SNI). The analgesic effect of ZOE after oral administration was assessed by measuring mechanical and thermal allodynia in SNI mice. The mechanism of action of ZOE and its main constituents were investigated using spinal cords samples and in an in vitro model of neuroinflammation by ELISA, western blotting and immunofluorescence techniques. RESULTS: Oral administration of ZOE 200 mg kg-1 ameliorated mechanical and thermal allodynia in SNI mice, with a rapid and a long-lasting effect. ZOE did not alter locomotor activity. In BV2 cells and spinal cord samples, ZOE, 6-gingerol and 6-shogaol reduced pERK levels, whereas ZOE and terpene fraction reduced HDAC1 protein levels, inhibited NF-κB signalling activation and decreased IL-1ß, TNF-α and IL-6 release. ZOE and each tested constituent had a positive effect on inflammation-impaired SH-SY5Y cell viability. CONCLUSIONS: The oral administration of ZOE attenuated SNI-induced neuropathic pain symptoms by reducing spinal neuroinflammation, suggesting ZOE as a novel and interesting candidate for the management of neuropathic pain.


Assuntos
Analgésicos não Entorpecentes/farmacologia , Gengibre/química , Neuralgia/tratamento farmacológico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Administração Oral , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos não Entorpecentes/química , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Histona Desacetilase 1/metabolismo , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos , Neuralgia/metabolismo , Extratos Vegetais/administração & dosagem , Rizoma/química , Medula Espinal/efeitos dos fármacos
8.
Expert Opin Pharmacother ; 21(11): 1377-1387, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32511032

RESUMO

INTRODUCTION: Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system, which can severely impact patients' quality of life. The current-approved treatments for NP comprise of both centrally acting agents and topical drugs, including capsaicin 8% dermal patches, which is approved for the treatment of peripheral NP. AREAS COVERED: The authors summarize literature data regarding capsaicin use in patients who suffer from NP and discuss the clinical applications of this topical approach. EXPERT OPINION: Overall, the capsaicin 8% dermal patch is as effective in reducing pain intensity as other centrally active agents (i.e. pregabalin). Some studies have also reported fewer systemic side effects, a faster onset of action and superior treatment satisfaction compared with systemic agents. In our opinion, capsaicin 8% dermal patches also present additional advantages, such as a good systemic tolerability, the scarcity of adverse events, the possibility to combine it with other agents, and a good cost-effective profile. It is important to note that, as the mechanism of action of capsaicin 8% is the 'defunctionalization' of small afferent fibers through interaction with TRPV1 receptors, the peripheral expression of this receptor on nociceptor fibers, is crucial to predict patient's response to treatment.


Assuntos
Analgésicos/administração & dosagem , Analgésicos/uso terapêutico , Capsaicina/administração & dosagem , Capsaicina/uso terapêutico , Neuralgia/tratamento farmacológico , Administração Tópica , Analgésicos/efeitos adversos , Capsaicina/efeitos adversos , Análise Custo-Benefício , Prova Pericial , Humanos , Neuralgia/metabolismo , Pregabalina/administração & dosagem , Pregabalina/efeitos adversos , Pregabalina/uso terapêutico , Qualidade de Vida , Canais de Cátion TRPV/metabolismo , Adesivo Transdérmico
9.
J Neuroimmunol ; 345: 577261, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32570135

RESUMO

The development and maintenance of neuropathic pain is now given far more attention in the clinic work. Increasing evidence has shown that colony-stimulating factor 1 (CSF1) is involved in microglial activation and may further induce pain. Here, we observed the signaling events that link the CSF1-induced microglial activated and consequences for pain processing. For the in vitro study, flow cytometry showed the microglial activity was markedly increased after CSF1 stimulation. Western blot showed the increased expression of p-PRKAA1/PRKAA1, p-AMPK/AMPK, p-ULK1/ULK1, p-S6k/S6k and LC3-II/LC3-I. QRT-PCR showed the IL-1, TNF-α and BDNF were simultaneously upregulated in the activated microglia cells, whereas the specific AMPK inhibitor compound C exhibited reverse effects in microglia. Using immunofluorescence staining and electron microscopy, we found CSF1 decreased microglial p62 expression and induced the number of autophagosomes, whereas compound C significantly exhibited the reverse effects. For the in vivo study, compared with the control and AMPK-siRNA transfection, the mice under CSF1 intrathecal injection increased CSF1 receptor and LC3 expressed in the activated spinal microglia. More importantly, qRT-PCR showed CSF1 intrathecal injection substantially upregulated BDNF and c-Fos mRNA expression as well as the ensuing neuropathic pain. Our findings demonstrated that CSF1 induced a significant upregulation of microglial activation via the AMPK signaling pathway and resulted in an increasing microglial autophagic level. An increasing CSF1 level in the central nervous system can mimic and cause pain syndromes by up-regulation of AMPK-depended autophagy, thus offering a new target for the therapy of neuropathic pain.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/fisiologia , Fator Estimulador de Colônias de Macrófagos/administração & dosagem , Microglia/metabolismo , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Animais , Autofagia/efeitos dos fármacos , Células Cultivadas , Injeções Espinhais , Fator Estimulador de Colônias de Macrófagos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Neuralgia/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
10.
Neurology ; 95(7): e805-e814, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32591473

RESUMO

OBJECTIVE: To determine whether cervical cord levels of metabolites are associated with pain sensation after spinal cord injury (SCI) by performing magnetic resonance spectroscopy in patients with SCI with and without neuropathic pain (NP). METHODS: Cervical cord single-voxel spectroscopic data of 24 patients with SCI (14 with NP, 10 pain-free) and 21 healthy controls were acquired at C2/3 to investigate metabolite ratios associated with neuroinflammation (choline-containing compounds to myoinositol [tCho/mI]) and neurodegeneration (total N-acetylaspartate to myo-inositol [tNAA/mI]). NP levels were measured, and Spearman correlation tests assessed associations between metabolite levels, cord atrophy, and pinprick score. RESULTS: In patients with NP, tCho/mI levels were increased (p = 0.024) compared to pain-free patients and negatively related to cord atrophy (p = 0.006, r = 0.714). Better pinprick score was associated with higher tCho/mI levels (p = 0.032, r = 0.574). In pain-free patients, tCho/mI levels were not related to cord atrophy (p = 0.881, r = 0.055) or pinprick score (p = 0.676, r = 0.152). tNAA/mI levels were similar in both patient groups (p = 0.396) and were not associated with pinprick score in patients with NP (p = 0.405, r = 0.242) and pain-free patients (p = 0.117, r = 0.527). CONCLUSIONS: Neuroinflammatory metabolite levels (i.e., tCho/mI) were elevated in patients with NP, its magnitude being associated with less cord atrophy and greater pain sensation (e.g., pinprick score). This suggests that patients with NP have more residual spinal tissue and greater metabolite turnover than pain-free patients. Neurodegenerative metabolite levels (i.e., tNAA/mI) were associated with greater cord atrophy but unrelated to NP. Identifying the metabolic NP signature provides new NP treatment targets and could improve patient stratification in interventional trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that levels of magnetic resonance spectroscopy-identified metabolites of neuroinflammation were elevated in patients with SCI with NP compared to those without NP.


Assuntos
Medula Cervical/metabolismo , Inflamação/metabolismo , Neuralgia/metabolismo , Traumatismos da Medula Espinal/metabolismo , Adulto , Atrofia/patologia , Medula Cervical/patologia , Colina/metabolismo , Creatina/metabolismo , Feminino , Humanos , Inflamação/complicações , Inositol/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neuralgia/complicações , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/fisiopatologia
11.
Pain Res Manag ; 2020: 1854363, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32351637

RESUMO

Objective: Neuropathic pain with complex mechanisms has become a major public health problem that greatly impacts patients' quality of life. Therefore, novel and more effective strategies against neuropathic pain need further investigation. Electroacupuncture (EA) has an ameliorating effect on neuropathic pain following spared nerve injury (SNI), but the underlying mechanism remains to be fully clarified. Interferon regulatory factor 8 (IRF8), a critical transcription factor, was reported to be involved in the modulation of neuropathic pain. Here, we focused on exploring whether 2 Hz EA stimulation exerts an inhibitory action on spinal IRF8 in SNI rats. Methods: In this study, SNI rats were treated with 2 Hz EA once every other day for 21 days. Paw withdrawal threshold (PWT) was applied to determine the analgesic effect of 2 Hz EA on SNI rats. The spinal IRF8 and CX3CRl expressions were detected with qRT-PCR and western blot, and immunofluorescence staining was used to evaluate colocation of IRF8 or CX3CRl with microglial activation marker CD11b in the spinal cord. Results: It was found that SNI induced significant elevation of spinal IRF8 and CX3CRl mRNA and protein expression. Additionally, immunofluorescence results showed that SNI elicited the coexpression of IRF8 with CD11b, as well as CX3CRl with CD11b in the spinal cord. Meanwhile, 2 Hz EA treatment of SNI rats not only reduced IRF8 and CX3CRl mRNA and protein expression, but also reversed the coexpression of IRF8 or CX3CRl with CD11b in the spinal cord, along with an attenuation of SNI-evoked mechanical hypersensitivity. Conclusion: This experiment highlighted that 2 Hz EA can inhibit IRF8 expression and microglial activation in the spinal cord of SNI rats. Hence, targeting IRF8 may be a promising therapeutic strategy for 2 Hz EA treatment of neuropathic pain.


Assuntos
Eletroacupuntura , Fatores Reguladores de Interferon/metabolismo , Neuralgia/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Medula Espinal/metabolismo , Animais , Masculino , Ratos , Ratos Sprague-Dawley
12.
Psychopharmacology (Berl) ; 237(8): 2509-2516, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32468099

RESUMO

RATIONALE: Ventrolateral orbital cortex (VLO) has been found to play an important role in the regulation of neuropathic pain (NPP). As a traditional mood stabilizer, valproic acid (VPA) is currently employed in the treatment of NPP. However, whether VPA plays an analgesic role in VLO is still unknown. OBJECTIVES: To elucidate the underlying analgesic mechanism of microinjection of VPA into the VLO on spared nerve injury (SNI), an animal model of NPP. METHODS: We firstly examined the role of VPA by intraperitoneal and intral-VLO injection. Then, we accessed its role as a histone deacetylase inhibitor by intral-VLO microinjection of sodium butyrate. Finally, the GABAergic mechanism was measured through the intra-VLO microinjection of several agonists and antagonists of various GABAergic receptor subtypes. RESULTS: Both intraperitoneal and intral-VLO injection of VPA attenuated SNI-induced mechanical allodynia. Microinjection of sodium butyrate, one of the histone deacetylase inhibitors, into the VLO attenuated the mechanical allodynia. Besides, microinjection of valpromide, a derivative of VPA which is a GABAergic agonist, into the VLO also attenuated allodynia. Furthermore, microinjection of picrotoxin, a GABAA receptor antagonist, into the VLO attenuated mechanical allodynia; microinjection of picrotoxin before VPA into the VLO increased VPA-induced anti-allodynia. Besides, microinjection of CGP 35348, a GABAB receptor antagonist, into the VLO attenuated allodynia; microinjection of CGP 35348 before VPA into the VLO also increased VPA-induced anti-allodynia. What is more, microinjection of imidazole-4-acetic acid (I4AA), a GABAC receptor antagonist, into the VLO enhanced allodynia; microinjection of I4AA before VPA into the VLO decreased VPA-induced anti-allodynia. CONCLUSIONS: These results suggest that both the histone acetylation mechanism and GABAergic system are involved in mediating VLO-induced anti-hypersensitivity.


Assuntos
Analgésicos/administração & dosagem , Modelos Animais de Doenças , GABAérgicos/administração & dosagem , Neuralgia/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Ácido Valproico/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Masculino , Microinjeções/métodos , Neuralgia/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley
13.
Brain Stimul ; 13(3): 774-782, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32289707

RESUMO

BACKGROUND: Behavioral alterations, like mechanical and thermal hyperalgesia, and modulation of biomarkers in the peripheral and central nervous systems (CNS) are markers of chronic pain. Transcranial direct current stimulation (tDCS) with exercise is a promising therapy for pain due to its neuromodulatory capacity. OBJECTIVE: To assess the individual effects of tDCS, exercise, and the two combined on the nociceptive response and BDNF, IL-1ß, and IL-4 levels in the CNS structures of rats in a chronic pain model. METHODS: For 8 consecutive days after the establishment of chronic neuropathic pain by inducing a constriction injury to the sciatic nerve (CCI), the rats received tDCS, exercise, or both treatments combined (20 min/day). The hyperalgesic response was assessed by von Frey and hot plate tests at baseline, 7, and 14 days after CCI surgery and immediately, 24 h, and 7 days after the end of treatment. The BDNF, IL-1ß, and IL-4 levels were assessed in the cerebral cortex, brainstem, and spinal cord by enzyme-linked immunosorbent assay at 48 h and 7 days after the end of treatment. RESULTS: The CCI model triggered marked mechanical and thermal hyperalgesia. However, bimodal tDCS, aerobic exercise, and the two combined relieved nociceptive behavior for up to 7 days following treatment completion. CONCLUSIONS: Bimodal tDCS, aerobic exercise, or both treatments combined promoted analgesic effects for neuropathic pain. Such effects were reflected by cytokine modulation throughout the spinal cord-brainstem-cerebral cortex axis.


Assuntos
Hiperalgesia/terapia , Mediadores da Inflamação/antagonistas & inibidores , Neuralgia/terapia , Condicionamento Físico Animal/métodos , Estimulação Transcraniana por Corrente Contínua/métodos , Animais , Encéfalo/metabolismo , Terapia Combinada/métodos , Hiperalgesia/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Neuralgia/metabolismo , Condicionamento Físico Animal/fisiologia , Ratos , Nervo Isquiático/lesões , Medula Espinal/metabolismo , Resultado do Tratamento
14.
PLoS One ; 15(4): e0231597, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32287325

RESUMO

Resident microglia of the central nervous system are being increasingly recognized as key players in diseases such as neuropathic pain. Biochemical and behavioral studies in neuropathic pain rodent models have documented compelling evidence of the critical role of ATP mediated-P2X4R-brain-derived neurotrophic factor (BDNF) signaling pathway in the initiation and maintenance of pain hypersensitivity, a feature driving neuropathic pain-related behavior. The goal of this study was to develop and characterize an in vitro cell line model of activated microglia that can be subsequently utilized for screening neuropathic pain therapeutics. In the present study, we characterized the SIM-A9 microglia cell line for key molecules in the P2X4R-BDNF signaling axis using a combination of biochemical techniques and developed an ATP-activated SIM-A9 microglia model. We present three novel findings: first, SIM-A9 cells expressed P2X4R and BDNF proteins, second, ATP, but not LPS, was cytocompatible with SIM-A9 cells and third, exposure of cells to optimized ATP concentrations for defined periods increased intracellular expression of Iba1 and BDNF proteins. Increased Iba1 levels confirmed microglia activation and increased BDNF expression confirmed ATP-mediated stimulation of the P2X4R signaling pathway. We propose that this ATP-activated SIM-A9 cell line model system can be utilized for screening both small- as well as macro-molecular neuropathic pain therapeutics targeting BDNF and/or P2X4R knockdown.


Assuntos
Microglia/metabolismo , Neuralgia/metabolismo , Transdução de Sinais , Trifosfato de Adenosina/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Técnicas de Cultura de Células/métodos , Lipopolissacarídeos/farmacologia , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Microglia/citologia , Microglia/efeitos dos fármacos , Neuralgia/patologia , Receptores Purinérgicos P2X4/genética , Receptores Purinérgicos P2X4/metabolismo
15.
Arch Biochem Biophys ; 685: 108330, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32156533

RESUMO

Switching microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype represents a novel therapeutic strategy for diabetic neuropathic pain (DNP). This study aims to determine the role and mechanism of interleukin (IL)-35 in regulating microglial M1/M2 polarization in DNP. A rat model of DNP was induced by a single streptozocin injection and recombinant IL-35 (rIL-35) was then intrathecally administered to the rats for 14 days. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured to assess the therapeutic effect of IL-35. Highly aggressive proliferating immortalized (HAPI), a rat microglia cell line, was treated with lipopolysaccharide (LPS) for M1 polarization or IL-4 for M2 polarization. The M1 markers (CD68, iNOS, TNF-α, IL-6) and M2 markers (CD206, Arg-1, IL-10) were examined. rIL-35 administration in DNP model rats elevated MWT and TWL, induced microglial polarization toward the M2 phenotype, suppressed JNK signaling and activated JAK2/STAT6 signaling. In vitro assay confirmed that rIL-35 induced microglial M2 polarization in HAPI cells through inhibiting JNK signaling and activating JAK2/STAT6 signaling. Collectively, the mechanism underlying therapeutic effect of IL-35 on DNP may relate to its promotion of microglial M2 polarization by regulating JNK signaling and JAK2/STAT6 signaling.


Assuntos
Neuropatias Diabéticas/metabolismo , Subunidade p35 da Interleucina-12/metabolismo , Microglia/metabolismo , Neuralgia/metabolismo , Animais , Linhagem Celular , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/complicações , Janus Quinase 2/metabolismo , MAP Quinase Quinase 4/metabolismo , Masculino , Neuralgia/induzido quimicamente , Neuralgia/complicações , Ratos Sprague-Dawley , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais/fisiologia , Estreptozocina
16.
Int J Mol Sci ; 21(6)2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32178439

RESUMO

While the descending dopaminergic control system is not fully understood, it is reported that the hypothalamic A11 nucleus is its principle source. To better understand the impact of this system, particularly the A11 nucleus, on neuropathic pain, we created a chronic constriction injury model of the infraorbital nerve (ION-CCI) in rats. ION-CCI rats received intraperitoneal administrations of quinpirole (a dopamine D2 receptor agonist). ION-CCI rats received microinjections of quinpirole, muscimol [a gamma-aminobutyric acid type A (GABAA) receptor agonist], or neurotoxin 6-hydroxydopamine (6-OHDA) into the A11 nucleus. A von Frey filament was used as a mechanical stimulus on the maxillary whisker pad skin; behavioral and immunohistochemical responses to the stimulation were assessed. After intraperitoneal administration of quinpirole and microinjection of quinpirole or muscimol, ION-CCI rats showed an increase in head-withdrawal thresholds and a decrease in the number of phosphorylated extracellular signal-regulated kinase (pERK) immunoreactive (pERK-IR) cells in the superficial layers of the trigeminal spinal subnucleus caudalis (Vc). Following 6-OHDA microinjection, ION-CCI rats showed a decrease in head-withdrawal thresholds and an increase in the number of pERK-IR cells in the Vc. Our findings suggest the descending dopaminergic control system is involved in the modulation of trigeminal neuropathic pain.


Assuntos
Nervos Cranianos/metabolismo , Dopamina/metabolismo , Traumatismos do Nervo Facial/metabolismo , Animais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Agonistas de Receptores de GABA-A/farmacologia , Hiperalgesia/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Muscimol/farmacologia , Neuralgia/metabolismo , Oxidopamina/farmacologia , Medição da Dor/métodos , Limiar da Dor/fisiologia , Fosforilação/efeitos dos fármacos , Quimpirol/farmacologia , Ratos , Ratos Wistar , Receptores de Dopamina D2/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Ácido gama-Aminobutírico/metabolismo
17.
Int J Mol Sci ; 21(4)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093166

RESUMO

Neuropathic pain conditions including neuropathic orofacial pain (NOP) are difficult to treat. Contemporary therapeutic agents for neuropathic pain are often ineffective in relieving pain and are associated with various adverse effects. Finding new options for treating neuropathic pain is a major priority in pain-related research. Cannabinoid-based therapeutic strategies have emerged as promising new options. Cannabinoids mainly act on cannabinoid 1 (CB1) and 2 (CB2) receptors, and the former is widely distributed in the brain. The therapeutic significance of cannabinoids is masked by their adverse effects including sedation, motor impairment, addiction and cognitive impairment, which are thought to be mediated by CB1 receptors in the brain. Alternative approaches have been developed to overcome this problem by selectively targeting CB2 receptors, peripherally restricted CB1 receptors and endocannabinoids that may be locally synthesized on demand at sites where their actions are pertinent. Many preclinical studies have reported that these strategies are effective for treating neuropathic pain and produce no or minimal side effects. Recently, we observed that inhibition of degradation of a major endocannabinoid, 2-arachydonoylglycerol, can attenuate NOP following trigeminal nerve injury in mice. This review will discuss the above-mentioned alternative approaches that show potential for treating neuropathic pain including NOP.


Assuntos
Sistemas de Liberação de Medicamentos , Endocanabinoides/metabolismo , Inibidores Enzimáticos/uso terapêutico , Dor Facial , Neuralgia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores , Animais , Dor Facial/tratamento farmacológico , Dor Facial/metabolismo , Dor Facial/patologia , Humanos , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Neuralgia/patologia
18.
Int J Mol Sci ; 21(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32070010

RESUMO

: The mechanical head-withdrawal threshold (MHWT) was significantly reduced following inferior alveolar nerve transection (IANX) in rats. Nitrate and nitrite synthesis was dramatically increased in the trigeminal ganglion (TG) at 6 h after the IANX. The relative number of neuronal nitric oxide synthase (nNOS)-immunoreactive (IR) cells was significantly higher in IANX rats compared to sham-operated and N-propyl-L-arginine (NPLA)-treated IANX rats. On day 3 after NPLA administration, the MHWT recovered considerably in IANX rats. Following L-arginine injection into the TG, the MHWT was significantly reduced within 15 min, and the mean number of TG cells encircled by glial fibrillary acidic protein (GFAP)-IR cells was substantially higher. The relative number of nNOS-IR cells encircled by GFAP-IR cells was significantly increased in IANX rats. In contrast, after NPLA injection into the TG, the relative number of GFAP-IR cells was considerably reduced in IANX rats. Fluorocitrate administration into the TG significantly reduced the number of GFAP-IR cells and prevented the MHWT reduction in IANX rats. The present findings suggest that following IANX, satellite glial cells are activated via nitric oxide (NO) signaling from TG neurons. The spreading satellite glial cell activation within the TG results in mechanical hypersensitivity of face regions not directly associated with the trigeminal nerve injury.


Assuntos
Proteína Glial Fibrilar Ácida/genética , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico/genética , Células Satélites de Músculo Esquelético/metabolismo , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Modelos Animais de Doenças , Humanos , Hiperalgesia/genética , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Nervo Mandibular/metabolismo , Nervo Mandibular/patologia , Traumatismos do Nervo Mandibular/tratamento farmacológico , Traumatismos do Nervo Mandibular/metabolismo , Traumatismos do Nervo Mandibular/patologia , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Neuralgia/patologia , Neuroglia/metabolismo , Ratos , Ratos Sprague-Dawley , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Transdução de Sinais/genética , Gânglio Trigeminal/efeitos dos fármacos , Gânglio Trigeminal/patologia , Traumatismos do Nervo Trigêmeo/genética , Traumatismos do Nervo Trigêmeo/metabolismo , Traumatismos do Nervo Trigêmeo/patologia
19.
Exp Neurol ; 327: 113240, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32045596

RESUMO

The voltage sodium channel 1.8 (NaV1.8) in the dorsal root ganglion (DRG) neurons contributes to the initiation and development of chronic inflammatory and neuropathic pain. However, an effective intervention on NaV1.8 remains to be studied in pre-clinical research and clinical trials. In this study, we aimed to investigate whether transcription factor 4 (TCF4) overexpression represses NaV1.8 expression in DRG neurons, thus preventing the development of chronic pain. Using chromatin immunoprecipitation (CHIP), we verified the interaction of TCF4 and sodium voltage-gated channel alpha subunit 10A (SCN10A) enhancer in HEK293 cells and rat DRG neurons. Using a dual luciferase reporter assay, we confirmed the transcriptional inhibition of TCF4 on SCN10A promoter in vitro. To investigate the regulation of TCF4 on Nav1.8, we then upregulated TCF4 expression by intrathecally delivering an overexpression of recombinant adeno-associated virus (rAAV) in the Complete Freund's adjuvant (CFA)-induced inflammatory pain model and spared nerve injury (SNI)-induced neuropathic pain model. By using a quantitative polymerase chain reaction (qPCR), western blot, and immunostaining, we evaluated NaV1.8 expression after a noxious stimulation and the application of the TCF4 overexpression virus. We showed that the intrathecal delivery of TCF4 overexpression virus significantly repressed the increase of NaV1.8 and prevented the development of hyperalgesia in rats. Moreover, we confirmed the efficient role of an overexpressed TCF4 in preventing the CFA- and SNI-induced neuronal hyperexcitability by calcium imaging. Our results suggest that attenuating the dysregulation of NaV1.8 by targeting TCF4 may be a novel therapeutic strategy for chronic inflammatory and neuropathic pain.


Assuntos
Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Neuralgia/metabolismo , Neurônios/metabolismo , Fator de Transcrição 4/metabolismo , Animais , Regulação para Baixo , Células HEK293 , Humanos , Hiperalgesia/genética , Inflamação/genética , Inflamação/metabolismo , Masculino , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Neuralgia/genética , Limiar da Dor/fisiologia , Ratos , Ratos Sprague-Dawley , Fator de Transcrição 4/genética , Regulação para Cima
20.
Int J Mol Sci ; 21(3)2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32024024

RESUMO

Numerous studies have verified that electroacupuncture (EA) can relieve neuropathic pain through a variety of mechanisms. Synaptotagmin 1 (Syt-1), a synaptic vesicle protein for regulating exocytosis of neurotransmitters, was found to be affected by EA stimulation. However, the roles of Syt-1 in neuropathic pain and EA-induced analgesic effect remain unclear. Here, the effect of Syt-1 on nociception was assessed through an antibody blockade, siRNA silencing, and lentivirus-mediated overexpression of spinal Syt-1 in rats with spared nerve injury (SNI). EA was used for stimulating bilateral "Sanjinjiao" and "Zusanli" acupoints of the SNI rats to evaluate its effect on nociceptive thresholds and spinal Syt-1 expression. The mechanically and thermally nociceptive behaviors were assessed with paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) at different temperatures, respectively, at day 0, 7, 8, 14, and 20. Syt-1 mRNA and protein levels were determined with qRT-PCR and Western blot, respectively, and its distribution was observed with the immunohistochemistry method. The results demonstrated Syt-1 antibody blockade and siRNA silencing increased ipsilateral PWTs and PWLs of SNI rats, while Syt-1 overexpression decreased ipsilateral PWTs and PWLs of rats. EA significantly attenuated nociceptive behaviors and down-regulated spinal Syt-1 protein levels (especially in laminae I-II), which were reversed by Syt-1 overexpression. Our findings firstly indicate that Syt-1 is involved in the development of neuropathic pain and that EA attenuates neuropathic pain, probably through suppressing Syt-1 protein expression in the spinal cord.


Assuntos
Eletroacupuntura/métodos , Neuralgia/terapia , Sinaptotagmina I/genética , Sinaptotagmina I/metabolismo , Pontos de Acupuntura , Animais , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Neuralgia/genética , Neuralgia/metabolismo , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...