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1.
J Cancer Res Ther ; 16(1): 34-39, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362607

RESUMO

Background and Objective: Metformin (MET) has been used as an antidiabetic agent for type II diabetes. At the same time, recent researches have shown that the clinical improvement of MET is useful for nerve damage. In this study, we investigated the analgesic effect of MET in paclitaxel (PAC)-induced neuropathic pain. Materials and Methods: Forty-two adult, female rats, Wistar strain weighing 220 ± 10 g were randomly divided into 5 experimental groups. PAC was intraperitoneally (IP) administered (2.0 mg/kg) for 4 groups every other day (0, 2, 4, and 6 days). By the 30th day, MET (100, 200, and 400 mg/kg) was administered to 4 groups. Before and after treatment, basal pain threshold values were measured with Randall-Selitto analgesiometer test. At the end of experiment, pathological values were measured in selected regions including brain (motor cortex, M1), spinal cord (L4-L5), sciatic nerve, and muscle. Results: According to our results, PAC-induced neuropathic pain reached to highest level at 14th day. Four hundred milligram/kilogram concentration of MET remarkably decreased PAC-induced neuropathic pain. On the other hand, pathologic features have shown that PAC had significant pathological change in the brain and spinal cord while in the peripheral nerves and muscles had not shown any pathological change. Conclusion: The pathological results of the current study for the first time demonstrated that MET beside of its antidiabetic effects reversed neuropathic pain induced by PAC. Consequently, this research can be promising for cancer patients that suffering from neuropathic pain induced by anticancer drugs.


Assuntos
Analgésicos/farmacologia , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Neoplasias/complicações , Neuralgia/prevenção & controle , Paclitaxel/efeitos adversos , Limiar da Dor/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Modelos Animais de Doenças , Feminino , Neoplasias/patologia , Neuralgia/induzido quimicamente , Neuralgia/patologia , Ratos , Ratos Wistar
2.
Proc Natl Acad Sci U S A ; 117(18): 10045-10054, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32312820

RESUMO

Although pain is a prevalent nonmotor symptom in Parkinson's disease (PD), it is undertreated, in part because of our limited understanding of the underlying mechanisms. Considering that the basal ganglia are implicated in pain sensation, and that their synaptic outputs are controlled by the subthalamic nucleus (STN), we hypothesized that the STN might play a critical role in parkinsonian pain hypersensitivity. To test this hypothesis, we established a unilateral parkinsonian mouse model with moderate lesions of dopaminergic neurons in the substantia nigra. The mice displayed pain hypersensitivity and neuronal hyperactivity in the ipsilesional STN and in central pain-processing nuclei. Optogenetic inhibition of STN neurons reversed pain hypersensitivity phenotypes in parkinsonian mice, while hyperactivity in the STN was sufficient to induce pain hypersensitivity in control mice. We further demonstrated that the STN differentially regulates thermal and mechanical pain thresholds through its projections to the substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi)/ventral pallidum (VP), respectively. Interestingly, optogenetic inhibition of STN-GPi/STN-VP and STN-SNr projections differentially elevated mechanical and thermal pain thresholds in parkinsonian mice. In summary, our results support the hypothesis that the STN and its divergent projections play critical roles in modulating pain processing under both physiological and parkinsonian conditions, and suggest that inhibition of individual STN projections may be a therapeutic strategy to relieve distinct pain phenotypes in PD.


Assuntos
Neurônios/fisiologia , Dor/fisiopatologia , Doença de Parkinson/fisiopatologia , Núcleo Subtalâmico/fisiopatologia , Animais , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/fisiopatologia , Modelos Animais de Doenças , Antagonistas de Dopamina/farmacologia , Globo Pálido/efeitos dos fármacos , Humanos , Hipersensibilidade , Camundongos , Neurônios/efeitos dos fármacos , Oxidopamina/farmacologia , Dor/complicações , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Doença de Parkinson/complicações , Substância Negra/fisiopatologia , Núcleo Subtalâmico/efeitos dos fármacos
3.
J Neurosci ; 40(18): 3517-3532, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32245829

RESUMO

One of the first signs of viral infection is body-wide aches and pain. Although this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization is well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-ß) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double-stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENT It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type I interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity.


Assuntos
Viroses do Sistema Nervoso Central/metabolismo , Interferon Tipo I/toxicidade , Nociceptores/metabolismo , Limiar da Dor/fisiologia , Dor/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Animais , Células Cultivadas , Viroses do Sistema Nervoso Central/induzido quimicamente , Viroses do Sistema Nervoso Central/patologia , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Nociceptores/efeitos dos fármacos , Nociceptores/patologia , Dor/induzido quimicamente , Dor/patologia , Limiar da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia
4.
Behav Pharmacol ; 31(2&3): 293-307, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32168028

RESUMO

Social environment influences the trajectory of developing opioid use disorder (OUD). Thus, the present study tested the hypothesis that sociability levels will affect the responses to opioids. Mice were tested for their baseline sociability, anxiety levels, pain sensitivities, and their acute locomotor response to 5 mg/kg opioids. Then, they were administered repeatedly with saline, hydrocodone, or morphine (20 mg/kg for 5 days, and then 40 mg/kg for 5 days). Subsequently, they were examined for the expression of locomotor sensitization and retested for the effects of opioids on their sociability, anxiety levels, and pain sensitivity. On the basis of their baseline sociability level, mice were divided into socially avoiding and socially exploring. Socially avoiding and socially exploring mice did not differ in their baseline weight and anxiety sensitivities. Socially avoiding mice had slightly higher baseline heat sensitivity than those in socially exploring mice. Repeated administration of opioids had differential effects in socially avoiding and socially exploring mice. In both social groups, repeated morphine administration had overall stronger effects compared with hydrocodone. Morphine-treated socially exploring mice developed greater locomotor sensitization than those in morphine-treated socially avoiding mice. Morphine-treated socially avoiding mice, but not socially exploring mice, spent more time in the center zone of the open-field test and in the light zone of light/dark boxes, and developed heat hyperalgesia. This study suggests that socially exploring animals are more sensitive to the sensitizing effects of opioids. In contrast, opioids have greater effects on the stress and pain systems of socially avoiding animals. Thus, the underlying mechanisms for developing OUD might differ in individuals with various sociability levels.


Assuntos
Analgésicos Opioides/farmacologia , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Transtornos Relacionados ao Uso de Opioides/psicologia , Animais , Ansiedade/fisiopatologia , Relação Dose-Resposta a Droga , Hidrocodona/farmacologia , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfina/farmacologia , Dor/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Meio Social
5.
Gene ; 742: 144583, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32184167

RESUMO

BACKGROUND: Studies showed that increased let-7b-5p microRNA during repeated electroacupuncture (EA) treatment was associated the formation of EA tolerance, which manifested as gradually decreased nociceptive threshold. Proenkephalin (PENK) is the precursor of enkephalin which is a pivot neuropeptide responsible for the decreased nociceptive threshold in EA. The aim of this study was to evaluate the relationship between let-7b-5p and PENK in EA tolerance. METHODS: The target gene of let-7b-5p microRNA was determined through the dual-luciferase reporter assay in cortical neurons. Seventy-two Sprague Dawley rats received a combination of EA and intracerebroventricular injection of microRNA (let-7b-5p agomir, antagomir or their controls). The nociceptive thresholds were assessed with radiant heat tail-flick method. PENK and let-7b-5p were measured with Western Blot and qPCR, respectively, after administration of let-7b-5p agomir, antagomir, and their controls at day 1, 4 and 7. RESULTS: Let-7b-5p targeted the 3' untranslated region of Penk1. The nociceptive thresholds in Let-7b-5p agomir + EA group were decreased (p < 0.05) compared with those in Let-7b-5p antagomir + EA group at day 1 to 7. Compared with Let-7b-5p agomir + EA group, the expression level of PENK in Let-7b-5p antagomir + EA group was increased at days 1, 4, and 7 (p < 0.05) CONCLUSION: Let-7b-5p may be a new potential target for decreasing the EA tolerance effect and facilitating the application of EA in treating chronic nociception of patients.


Assuntos
Eletroacupuntura , Encefalinas/genética , MicroRNAs/metabolismo , Dor Nociceptiva/terapia , Precursores de Proteínas/genética , Animais , Antagomirs/administração & dosagem , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Humanos , Injeções Intraventriculares , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/diagnóstico , Dor Nociceptiva/genética , Dor Nociceptiva/imunologia , Limiar da Dor/efeitos dos fármacos , Ratos
6.
Psychopharmacology (Berl) ; 237(5): 1545-1555, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32114633

RESUMO

RATIONALE: Over the last decade, oxycodone has become one of the most widely abused drugs in the USA. Oxycodone use disorder (OUD) is a serious health problem that has prompted a need to develop animal models of OUD that have both face and predictive validity. Oxycodone use in humans is more prevalent in women and leads to pronounced hyperalgesia and irritability during withdrawal. However, unclear is whether current animal models of oxycodone self-administration recapitulate these characteristics in humans. OBJECTIVES: We assessed the face validity of a model of extended-access oxycodone self-administration in rats by examining the escalation of oxycodone intake and behavioral symptoms of withdrawal, including irritability-like behavior and mechanical nociception, in male and female Wistar rats. RESULTS: Both male and female rats escalated their oxycodone intake over fourteen 12-h self-administration sessions. After escalation, female rats administered more drug than male rats. No differences in plasma oxycodone levels were identified, but males had a significantly higher level of oxycodone in the brain at 30 min. Extended access to oxycodone significantly decreased aggressive-like behavior and increased defensive-like behaviors when tested immediately after a 12-h self-administration session, followed by a rebound increase in aggressive-like behavior 12 h into withdrawal. Tests of mechanical nociception thresholds during withdrawal indicated pronounced hyperalgesia. No sex differences in irritability-like behavior or pain sensitivity were observed. CONCLUSIONS: The present study demonstrated the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and pronounced changes in pain and affective states.


Assuntos
Analgésicos Opioides/administração & dosagem , Oxicodona/administração & dosagem , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/psicologia , Caracteres Sexuais , Síndrome de Abstinência a Substâncias/psicologia , Analgésicos Opioides/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Emoções/efeitos dos fármacos , Emoções/fisiologia , Feminino , Masculino , Oxicodona/efeitos adversos , Limiar da Dor/fisiologia , Ratos , Ratos Wistar , Autoadministração , Síndrome de Abstinência a Substâncias/metabolismo
7.
Muscle Nerve ; 61(5): 662-670, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32083755

RESUMO

INTRODUCTION: We investigated the mechanisms underlying immobilization-induced muscle pain in rats. METHODS: In rat skeletal muscle, pressure pain threshold (PPT) of the gastrocnemius muscle was measured, and nerve growth factor (NGF) level, peripheral nerve fiber density, macrophage number, and interleukin-1ß (IL-1ß) mRNA expression were examined. An NGF receptor inhibitor was injected intramuscularly to assess the relationship between PPT and NGF levels. RESULTS: Immobilization resulted in a decrease in PPT and increases in NGF level, C-fiber density, M1 macrophage number, and IL-1ß mRNA expression. Injection of NGF receptor inhibitor reversed the decrease in PPT. DISCUSSION: NGF upregulation may be a major contributor to immobilization-induced muscle pain. The increases in C-fiber density, M1 macrophage number, and IL-1ß mRNA expression may be related to immobilization-induced muscle pain.


Assuntos
Hiperalgesia/metabolismo , Imobilização , Interleucina-1beta/genética , Macrófagos/patologia , Músculo Esquelético/metabolismo , Fator de Crescimento Neural/metabolismo , Limiar da Dor/fisiologia , RNA Mensageiro/metabolismo , Animais , Carbazóis/farmacologia , Moldes Cirúrgicos , Inibidores Enzimáticos/farmacologia , Membro Posterior , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Alcaloides Indólicos/farmacologia , Masculino , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Fibras Nervosas/patologia , Fibras Nervosas Amielínicas/patologia , Limiar da Dor/efeitos dos fármacos , Pressão , Distribuição Aleatória , Ratos , Ratos Wistar , Receptor trkA/antagonistas & inibidores
8.
Eur J Med Chem ; 188: 111920, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901745

RESUMO

γ-Aminobutyric acid (GABA) uptake transporters are membrane transport proteins that are involved in the pathophysiology of a number of neurological disorders. Some types of chronic pain appear to result from the dysfunction of the GABAergic system. The deficiency of mouse GAT1 transporter (mGAT1) abolishes the nociceptive response, which means that mGAT1 inhibition is an appropriate medical approach to achieve analgesia. The mGAT4 transporter is the second most abundant GAT subtype in the brain; however, its physiological role has not yet been fully understood in the central nervous system. In this study, we examined whether the combination of mGAT1 and mGAT3/mGAT4 inhibition in a single molecule might lead to potentially synergistic effects improving analgesic activity to relieve neuropathic pain. To study this hypothesis, new GABA uptake inhibitors were designed, synthesized, and evaluated in terms of their activity and subtype selectivity for mGAT1-4. Among new functionalized amino acid derivatives of serine and GABA analogs, compounds with preferential mGAT3/4 inhibitory activity were discovered. Two selected hits (19b and 31c) were subjected to in vivo tests. We found a statistically significant antiallodynic activity in the von Frey test in diabetic and oxaliplatin-induced neuropathic pain model. The novel compounds (4-hydroxybutanoic, 4-hydroxypentanoic, and 4-aminobutanoic acid derivatives and serine analogs) provide new insights into the structure-activity relationship of mGAT3/mGAT4 inhibitors and indicate a new direction in the search for potential treatment of neuropathic pain of various origin.


Assuntos
Analgésicos/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Captação de GABA/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Limiar da Dor/efeitos dos fármacos , Analgésicos/síntese química , Analgésicos/metabolismo , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Proteínas da Membrana Plasmática de Transporte de GABA/química , Inibidores da Captação de GABA/síntese química , Inibidores da Captação de GABA/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/etiologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Neuralgia/induzido quimicamente , Neuralgia/etiologia , Oxaliplatina , Ligação Proteica , Estreptozocina , Relação Estrutura-Atividade
9.
Arthritis Rheumatol ; 72(1): 57-66, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350812

RESUMO

OBJECTIVE: To evaluate the antiinflammatory and analgesic effects of sepiapterin reductase (SPR) inhibition in a mouse model of inflammatory joint disease, and to determine whether urinary sepiapterin levels, as measured in mice and healthy human volunteers, could be useful as a noninvasive, translational biomarker of SPR inhibition/target engagement. METHODS: The collagen antibody-induced arthritis (CAIA) model was used to induce joint inflammation in mice. The effects of pharmacologic inhibition of SPR on thresholds of heat-, cold-, and mechanical-evoked pain sensitivity and on signs of inflammation were tested in mice with CAIA. In addition, mice and healthy human volunteers were treated with SPR inhibitors, and changes in urinary sepiapterin levels were analyzed by high-performance liquid chromatography. RESULTS: CAIA in mice was characterized by 2 phases: in the acute inflammation (early) phase, joint inflammation and heat-, mechanical-, and cold-induced pain hypersensitivity were present, while in the postinflammation (late) phase, no joint inflammation was observed but heat- and mechanical-induced hypersensitivity, but not cold hypersensitivity, were present. Inhibition of SPR in mice with CAIA significantly attenuated the heat-induced hyperalgesia in both phases, and the mechanical allodynia in the late phase. Signs of inflammation were unaffected by SPR inhibition. Urinary tetrahydrobiopterin levels, as a marker of inflammatory pain, were increased during inflammation in mice with CAIA (2-fold increase over controls; P < 0.05) and significantly reduced by SPR inhibition (P < 0.05 versus vehicle-treated mice). Increased urinary sepiapterin levels in the presence of SPR inhibition in both mice and healthy human volunteers were associated with high sensitivity (70-85%) and high specificity (82-88%) for the prediction of SPR inhibition/target engagement. CONCLUSION: SPR inhibition reduces the pain associated with joint inflammation, thus showing its potential utility as an analgesic strategy for inflammatory joint pain. In addition, SPR inhibition increases urinary sepiapterin levels, indicating the potential of this measurement as a noninvasive biomarker of target engagement of SPR inhibitors, such as sulfasalazine, a disease-modifying antirheumatic drug that is currently used as a first-line treatment for rheumatoid arthritis.


Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Antirreumáticos/farmacologia , Artrite Experimental/fisiopatologia , Hiperestesia/fisiopatologia , Articulações/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Pterinas/urina , Sulfassalazina/farmacologia , Adulto , Animais , Artrite Experimental/patologia , Biomarcadores/urina , Biopterina/análogos & derivados , Biopterina/urina , Cromatografia Líquida de Alta Pressão , Temperatura Baixa , Feminino , Membro Posterior , Temperatura Alta , Humanos , Articulações/patologia , Masculino , Camundongos
10.
Br J Anaesth ; 124(1): 92-100, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711605

RESUMO

BACKGROUND: Intravenous dexamethasone is thought to prolong the duration of peripheral nerve block, but the dose-response relationship remains unclear. The aim of this volunteer study was to evaluate the dose-response effect of i.v. dexamethasone on the prolongation of median nerve block. METHODS: In a double-blind, randomised controlled study, 18 volunteer subjects received two median nerve blocks separated by a washout period. One block was conducted alongside an infusion of saline and the other alongside i.v. dexamethasone 2, 4, or 8 mg. The primary outcome was time to return of normal pinprick sensation. Secondary outcomes included thermal quantitative sensory testing (QST) for the time to return of cold detection threshold (CDT), warm detection threshold (WDT), cold pain threshold (CPT), heat pain threshold (HPT), area under QST curves, grip strength, and the incidence of adverse effects. RESULTS: The primary outcome, time to recovery of pinprick sensation, was similar between volunteers receiving saline or i.v. dexamethasone, regardless of dose (P=0.99). The time to recovery of QST milestones was similar between groups, although area under QST curves indicated prolongation of CDT (0 vs 8 mg, P=0.002) and WDT (0 vs 2 mg, P=0.008; 0 vs 4 mg, P=0.001; 0 vs 8 mg, P<0.001). There was no difference in motor recovery or adverse effects. CONCLUSIONS: Intravenous dexamethasone failed to significantly prolong the duration of pinprick anaesthesia regardless of dose. However, area under QST curve analysis indicated a dose-independent prolongation of CDT and WDT, the clinical significance of which is unclear. CLINICAL TRIAL REGISTRATION: NCT02864602 (clinicaltrials.gov).


Assuntos
Adjuvantes Anestésicos , Dexametasona , Bloqueio Nervoso/métodos , Nervos Periféricos , Adjuvantes Anestésicos/administração & dosagem , Adjuvantes Anestésicos/efeitos adversos , Administração Intravenosa , Adulto , Estudos Cross-Over , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Força da Mão , Voluntários Saudáveis , Humanos , Masculino , Nervo Mediano , Pessoa de Meia-Idade , Bloqueio Nervoso/efeitos adversos , Limiar da Dor/efeitos dos fármacos , Sensação/efeitos dos fármacos , Sensação Térmica/efeitos dos fármacos , Adulto Jovem
11.
Anesth Analg ; 130(1): 248-257, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31166231

RESUMO

BACKGROUND: Persistent use of prescription opioids beyond the period of surgical recovery is a large part of a public health problem linked to the current opioid crisis in the United States. However, few studies have been conducted to examine whether morphine reward is influenced by acute pain and injury. METHODS: In a mouse model of incisional injury and minor trauma, animals underwent conditioning, extinction, and drug-primed reinstatement with morphine to examine the rewarding properties of morphine in the presence of acute incisional injury and drug-induced relapse, respectively. In addition, we sought to determine whether these behaviors were influenced by kappa opioid receptor signaling and measured expression of prodynorphin messenger RNA in the nucleus accumbens and medial prefrontal cortex after conditioning and before reinstatement with morphine and incisional injury. RESULTS: In the presence of incisional injury, we observed enhancement of morphine reward with morphine-conditioned place preference but attenuated morphine-primed reinstatement to reward. This adaptation was not present in animals conditioned 12 days after incisional injury when nociceptive sensitization had resolved; however, they showed enhancement of morphine-primed reinstatement. Prodynorphin expression was greatly enhanced in the nucleus accumbens and medial prefrontal cortex of mice with incisional injury and morphine conditioning and remained elevated up to drug-primed reinstatement. These changes were not observed in mice conditioned 12 days after incisional injury. Further, kappa opioid receptor blockade with norbinaltorphimine before reinstatement reversed the attenuation induced by injury. CONCLUSIONS: These findings suggest enhancement of morphine reward as a result of incisional injury but paradoxically a protective adaptation with incisional injury from drug-induced relapse resulting from kappa opioid receptor activation in the reward circuitry. Remote injury conferred no such protection and appeared to enhance reinstatement.


Assuntos
Dor Aguda/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Morfina/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides kappa/agonistas , Recompensa , Ferimentos Penetrantes/tratamento farmacológico , Dor Aguda/metabolismo , Dor Aguda/fisiopatologia , Dor Aguda/psicologia , Animais , Condicionamento Psicológico/efeitos dos fármacos , Modelos Animais de Doenças , Encefalinas/genética , Encefalinas/metabolismo , Extinção Psicológica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Limiar da Dor/efeitos dos fármacos , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Receptores Opioides kappa/metabolismo , Transdução de Sinais , Ferimentos Penetrantes/metabolismo , Ferimentos Penetrantes/fisiopatologia , Ferimentos Penetrantes/psicologia
12.
Am J Physiol Renal Physiol ; 318(2): F298-F314, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31790304

RESUMO

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common chronic pelvic disorder with sensory symptoms of urinary urgency, frequency, and pain, indicating a key role for hypersensitivity of bladder-innervating sensory neurons. The inflammatory mast cell mediator histamine has long been implicated in IC/BPS, yet the direct interactions between histamine and bladder afferents remain unclear. In the present study, we show, using a mouse ex vivo bladder afferent preparation, that intravesical histamine enhanced the mechanosensitivity of subpopulations of afferents to bladder distension. Histamine also recruited "silent afferents" that were previously unresponsive to bladder distension. Furthermore, in vivo intravesical histamine enhanced activation of dorsal horn neurons within the lumbosacral spinal cord, indicating increased afferent signaling in the central nervous system. Quantitative RT-PCR revealed significant expression of histamine receptor subtypes (Hrh1-Hrh3) in mouse lumbosacral dorsal root ganglia (DRG), bladder detrusor smooth muscle, mucosa, and isolated urothelial cells. In DRG, Hrh1 was the most abundantly expressed. Acute histamine exposure evoked Ca2+ influx in select populations of DRG neurons but did not elicit calcium transients in isolated primary urothelial cells. Histamine-induced mechanical hypersensitivity ex vivo was abolished in the presence of the histamine H1 receptor antagonist pyrilamine and was not present in preparations from mice lacking transient receptor potential vanilloid 1 (TRPV1). Together, these results indicate that histamine enhances the sensitivity of bladder afferents to distension via interactions with histamine H1 receptor and TRPV1. This hypersensitivity translates to increased sensory input and activation in the spinal cord, which may underlie the symptoms of bladder hypersensitivity and pain experienced in IC/BPS.


Assuntos
Cistite Intersticial/metabolismo , Histamina/administração & dosagem , Hiperalgesia/metabolismo , Mecanorreceptores/efeitos dos fármacos , Mecanotransdução Celular/efeitos dos fármacos , Receptores Histamínicos H1/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Bexiga Urinária/inervação , Administração Intravesical , Animais , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Cistite Intersticial/fisiopatologia , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Hiperalgesia/fisiopatologia , Masculino , Mecanorreceptores/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Limiar da Dor/efeitos dos fármacos , Pressão , Receptores Histamínicos H1/metabolismo , Canais de Cátion TRPV/deficiência , Canais de Cátion TRPV/genética , Urotélio/efeitos dos fármacos , Urotélio/metabolismo
13.
J Ethnopharmacol ; 248: 112349, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31756450

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Arenga pinnata (Wurmb) Merr. is a medicinal and edible plant belonging to family Palmae. The fruits of this plant were used in traditional folk medicine due to its analgesia and anti-inflammatory activities. This study aimed to investigate the analgesic and anti-inflammatory properties and the mechanism of the ethanol extract of A. pinnata (Wurmb) Merr. fruit (EAF) on different experimental models. MATERIALS AND METHODS: High-performance liquid chromatography (HPLC) was used to determine the chromatographic profile and to analyze the composition of EAF. In the acute toxicity test, all mice were orally administered EAF at a maximum dosage of 26 g/kg and were then monitored for 14 days. The potential analgesic activity of EAF was evaluated by using animal pain models, namely the acetic acid-induced writhing test and the hot plate test in mice. The underlying mechanisms of analgesia were determined by pretreating with naloxone, capsaicin and cinnamaldehyde to evaluate the involvement of the opioid system and transient receptor potential channels (TRP channels). The anti-inflammatory activity of EAF was evaluated by using the following inflammatory animal models: xylene-induced ear edema in mice and Complete Freund's adjuvant (CFA)-induced paw swelling in rats. EAF was orally administered at the doses of 1.625, 3.25 and 6.5 g/kg in mice and 1.125, 2.25 and 4.5 g/kg in rats. The underlying mechanism of the anti-inflammatory activity was determined by enzyme-linked immunosorbent assay (ELISA) kits and real time-PCR used to measure the expression levels of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2). Western blot analysis was used to determine the expression levels of proteins related to the nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathways in paw tissues. RESULTS: Five compounds, namely (5-(hydroxymethyl) furan-2-yl) methanediol,4'-hydroxy-N-(4-hydroxy-3-methoxybenzoyl)-3',5'-dimethoxybenzamide, (+)-lyonirenisol-3a-O-ß-D-glucopyranoside, (-)-lyonirenisol-3a-O-ß-glucopyranoside and liquiritin, were firstly identified from A. pinnata (Wurmb) Merr. fruit by HPLC-UV analysis. In the acute toxicity test, no treatment-related toxicological signs or mortality was observed in mice administered doses up to 26 g/kg. Bodyweight was not obviously different among the treatment groups and the vehicle group. EAF significantly inhibited the pain response induced by acetic acid and increased the latency time in the hot plate test in mice. The anti-nociception effect of EAF in the formalin test was not alleviated by pretreatment with naloxone. However, the nociception induced by injection with capsaicin and cinnamaldehyde was significantly reduced by EAF. Compared with vehicle treatment, EAF significantly inhibited the formation of xylene-induced ear edema and CFA adjuvant-induced paw swelling. EAF markedly inhibited the production of IL-1ß, TNF-α, PGE2 and IL-6 induced by CFA in paw tissues. Furthermore, the phosphorylation of IKKα, IKKß, IκBα, p38, ERK1/2, and JNK and the nuclear translation of NF-κB p65 induced by CFA in paw tissues were significantly inhibited by EAF treatment compared with vehicle treatment. CONCLUSION: For the first time, this study provides pharmacological evidence for the analgesic and anti-inflammatory activities of EAF and the underlying mechanism, suggesting that EAF might be a potential candidate for reducing pain and inflammatory disorders.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Arecaceae , Edema/prevenção & controle , Etanol/química , Frutas , Inflamação/prevenção & controle , Dor/prevenção & controle , Extratos Vegetais/farmacologia , Solventes/química , Analgésicos/isolamento & purificação , Analgésicos/toxicidade , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/toxicidade , Arecaceae/química , Arecaceae/toxicidade , Citocinas/metabolismo , Modelos Animais de Doenças , Edema/metabolismo , Feminino , Frutas/química , Frutas/toxicidade , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Dor/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Ratos Sprague-Dawley
14.
Elife ; 82019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31713514

RESUMO

Nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate spinal interneurons that express the calcium-binding protein calretinin (CR). We show that these interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relay signals to lamina I projection neurons. Photoactivation of CR interneurons in vivo resulted in a significant nocifensive behavior that was morphine sensitive, caused a conditioned place aversion, and was enhanced by spared nerve injury. Furthermore, halorhodopsin-mediated inhibition of these interneurons elevated sensory thresholds. Our results suggest that dorsal horn circuits that involve excitatory CR neurons are important for the generation and amplification of pain and identify these interneurons as a future analgesic target.


Assuntos
Calbindina 2/genética , Interneurônios/metabolismo , Neuralgia/fisiopatologia , Neurônios/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Analgésicos Opioides/farmacologia , Animais , Calbindina 2/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Halorrodopsinas/genética , Halorrodopsinas/metabolismo , Interneurônios/efeitos dos fármacos , Interneurônios/patologia , Camundongos , Camundongos Transgênicos , Morfina/farmacologia , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Neuralgia/tratamento farmacológico , Neuralgia/genética , Neuralgia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Optogenética/métodos , Limiar da Dor/efeitos dos fármacos , Técnicas de Patch-Clamp , Estimulação Luminosa , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/patologia , Técnicas de Cultura de Tecidos , Transgenes
15.
Life Sci ; 239: 116961, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31654745

RESUMO

Neuropathic pain (NP) is a difficult condition to treat because of the modest efficacy of available drugs. New treatments are required. In the study we aimed to investigate the effects of the essential oil from Lippia grata alone or complexed in ß-cyclodextrin (LG or LG-ßCD) on persistent inflammatory and neuropathic pain in a mouse model. We also investigated Ca2+ currents in rat dorsal root ganglion (DRG) neurons. Male Swiss mice were treated with LG or LG/ß-CD (24 mg/kg, i.g.) and their effect was evaluated using an acute inflammatory pleurisy model and nociception triggered by intraplantar injection of an agonist of the TRPs channels. We also tested their effect in chronic pain models: injection of Freund's Complete Adjuvant and partial sciatic nerve ligation (PSNL). In the pleurisy model, LG reduced the number of leukocytes and the levels of TNF-α and IL-1ß. It also inhibited cinnamaldehyde and menthol-induced nociceptive behavior. The pain threshold in mechanical and thermal hyperalgesia was increased and paw edema was decreased in models of inflammatory and neuropathic pain. PSNL increased inflammatory protein contents and LG and LG-ßCD restored the protein contents of TNF-α, NF-κB, and PKA, but not IL-1ß and IL-10. LG inhibited voltage gated Ca2+ channels from DRG neurons. Our results suggested that LG or LG-ßCD produce anti-hyperalgesic effect in chronic pain models through reductions in TNF-α levels and PKA, and inhibited voltage-gated calcium channels and may be innovative therapeutic agents for the management of NP.


Assuntos
Hiperalgesia/tratamento farmacológico , Lippia/metabolismo , beta-Ciclodextrinas/farmacologia , Animais , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Hiperalgesia/metabolismo , Masculino , Camundongos , Neuralgia/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Óleos Voláteis/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Medição da Dor/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , beta-Ciclodextrinas/metabolismo
16.
Endocr Regul ; 53(1): 14-25, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517620

RESUMO

OBJECTIVE: Diabetes induces sensory symptoms of neuropathy as positive (hyperalgesia), negative (hypoalgesia), or both. METHODS: In the present study, fifty male Wistar rats were allocated to five groups: control, control+nitrate, diabetes, diabetes+insulin, and diabetes+nitrate. Thirty days after diabetes confirmation, insulin (2-4 U/day) was injected subcutaneously in diabetes+insulin group and nitrate (100 mg/l) was added into drinking water of the control+nitrate and diabetes+nitrate groups for a period of 2 months. In order to assess the mechanical and thermal algesia, tail immersion, hot plate, and von Frey tests were performed. The serum insulin levels were determined with insulin ELISA Kit. Serum level of NOx was determined by the Griess method. RESULTS: Both thermal and mechanical nociceptive thresholds showed a significant decrease (p<0.05) which was followed by a significant increase (p<0.01) in the thermal nociceptive threshold in the diabetes group. Chronic nitrate or insulin treatment led to a significant decrease (p<0.01) in blood glucose levels, as well as a significant (p<0.05) increase in the body weight and serum NOx. Moreover, nitrate treatment significantly increased serum insulin levels (p<0.001) compared to the other groups. CONCLUSION: Chronic nitrate treatment modified the thermal and mechanical sensitivities in diabetic animals.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Nitratos/farmacologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/patologia , Avaliação Pré-Clínica de Medicamentos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hiperalgesia/patologia , Masculino , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Nitratos/uso terapêutico , Nociceptividade/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Estreptozocina
17.
Physiol Res ; 68(5): 705-715, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31424251

RESUMO

Orofacial pain disorders are frequent in the general population and their pharmacological treatment is difficult and controversial. Therefore, the search for novel, safe and efficient analgesics is an important but still elusive goal for contemporary medicine. In the recent years, the antinociceptive potential of endocannabinoids and opioids has been emphasized. However, concerns for the safety of their use limit their clinical applications. the possibility of modulating the activity of endocannabinoids by regulation of their synthesis and/or degradation offers an innovative approach to the treatment of pain. A rat model of trigeminal pain, utilizing tongue jerks evoked by electrical tooth pulp stimulation during perfusion of the cerebral ventricles with various neurotransmitter solutions can be used in the pharmacological studies of nociception in the orofacial area. The aim of this review is to present the effects of pharmacological activity of opioids and endocannabinoids affecting the transmission of the sensory information from the orofacial area on the example of trigemino-hypoglossal reflex in rats.


Assuntos
Analgésicos Opioides/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Endocanabinoides/uso terapêutico , Dor Facial/tratamento farmacológico , Limiar da Dor/efeitos dos fármacos , Receptores de Canabinoides/efeitos dos fármacos , Receptores Opioides/agonistas , Animais , Endocanabinoides/metabolismo , Dor Facial/metabolismo , Dor Facial/fisiopatologia , Humanos , Peptídeos Opioides/metabolismo , Receptores de Canabinoides/metabolismo , Receptores Opioides/metabolismo , Reflexo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
18.
Physiol Res ; 68(5): 845-855, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31424261

RESUMO

Bortezomib (BTZ) is used as a chemotherapeutic agent for the treatment of multiple myeloma. Nevertheless, one of the significant limiting complications of BTZ is painful peripheral neuropathy during BTZ therapy. Thus, in this study we examined signaling pathways of interleukin-6 (IL-6) and transient receptor potential ankyrin 1 (TRPA1) in the sensory nerves responsible for neuropathic pain induced by BTZ and further determined if influencing the pathways can improve neuropathic pain. ELISA and western blot analysis were used to examine the levels of IL-6, and IL-6 receptor (IL-6R), TRPA1 and p38-MAPK and JNK signal in the lumbar dorsal root ganglion. Behavioral test was performed to determine mechanical and cold sensitivity in a rat model. Our results showed that systemic injection of BTZ increased mechanical pain and cold sensitivity as compared with control animals. Data also showed that protein expression of TRPA1 and IL-6R was upregulated in the dorsal root ganglion of BTZ rats and blocking TRPA1 attenuated mechanical and cold sensitivity in control rats and BTZ rats. Notably, the inhibitory effect of blocking TRPA1 was smaller in BTZ rats than that in control rats. In addition, a blockade of IL-6 signal attenuated intracellular p38-MAPK and JNK in the sensory neuron. This also decreased TRPA1 expression and alleviated mechanical hyperalgesia and cold hypersensitivity in BTZ rats. In conclusion, we revealed specific signaling pathways leading to neuropathic pain induced by chemotherapeutic BTZ, including IL-6-TRPA1, suggesting that blocking these signals is beneficial to alleviate neuropathic pain during BTZ intervention.


Assuntos
Acetanilidas/farmacologia , Analgésicos/farmacologia , Bortezomib , Gânglios Espinais/efeitos dos fármacos , Interleucina-6/antagonistas & inibidores , Neuralgia/tratamento farmacológico , Inibidores de Proteassoma , Purinas/farmacologia , Pirazinas/farmacologia , Quinoxalinas/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Canal de Cátion TRPA1/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Fosforilação , Ratos Sprague-Dawley , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/metabolismo , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais , Canal de Cátion TRPA1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
World Neurosurg ; 132: e529-e534, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31449993

RESUMO

BACKGROUND: Spinal cord injury (SCI) is a common type of injury, and about half of patients affected by SCI will suffer from neuropathic pain within a year after injury. However, the treatment effect of neuropathic pain is far from satisfactory. Our study attempted to reveal whether salvianolic acid B (SalB) could relieve the neuropathic pain caused by SCI in mice by inhibiting the Toll-like receptor 4 (TLR4)/Myeloid differentiation factor 88 (MyD88) pathway. METHODS: The mice were randomly divided into a sham group, model group, high-dose treatment group, and low-dose treatment group. The high- and low-dose groups received varying doses of SalB after modeling. RESULTS: The increase of pain sensitivity was evaluated by detecting paw withdrawal mechanical threshold and withdrawal thermal latency. Messenger RNA and protein expression levels of TLR4 and myD88 were detected by using quantitative reverse-transcription polymerase chain reaction and western blot, respectively. Compared with the model group, there was a significant reduction in paw withdrawal mechanical threshold and withdrawal thermal latency after SalB treatment. CONCLUSIONS: SalB reduced the release of tumor necrosis factor-α and substance P by inhibiting the TLR4/MyD88 pathway in the SCI mouse model. This not only resulted in lower pain, but also contributed to long-term relief of mechanical hyperalgesia.


Assuntos
Benzofuranos/farmacologia , Fator 88 de Diferenciação Mieloide/efeitos dos fármacos , Neuralgia/metabolismo , Limiar da Dor/efeitos dos fármacos , Traumatismos da Medula Espinal/metabolismo , Receptor 4 Toll-Like/efeitos dos fármacos , Animais , Hiperalgesia/etiologia , Hiperalgesia/imunologia , Hiperalgesia/metabolismo , Masculino , Camundongos , Neuralgia/etiologia , Neuralgia/imunologia , Distribuição Aleatória , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/imunologia
20.
Pain ; 160(8): 1719-1728, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31335642

RESUMO

Despite growing interest in the role of stress mediators in pain chronicity, the effects of the stress hormone cortisol on acute pain remain incompletely understood. In a randomized, double-blind, placebo-controlled study with N = 100 healthy volunteers, we tested the effects of oral hydrocortisone (20 mg) in 2 widely used pain models for the visceral and somatic modality. Salivary cortisol was increased in the hydrocortisone group (time × group: P < 0.001). For the visceral modality, assessed using pressure-controlled rectal distensions, hydrocortisone decreased the pain threshold from before to after treatment (time × group: P = 0.011), an effect primarily driven by women (time × sex: P = 0.027). For the somatic modality, cutaneous heat pain thresholds remained unaffected by hydrocortisone. Hydrocortisone did not alter perceived pain intensity or unpleasantness of either modality. Conditioned pain-related fear in response to predictive cues was only observed for the visceral modality (time × modality: P = 0.026), an effect that was significantly reduced by hydrocortisone compared with placebo (time × group: P = 0.028). This is the first psychopharmacological study to support that acutely increased cortisol enhances pain sensitivity and impairs pain-related emotional learning within the visceral, but not the somatic pain modality. Stress-induced visceral hyperalgesia and deficits in emotional pain-related learning could play a role in the pathophysiology of chronic visceral pain.


Assuntos
Emoções/efeitos dos fármacos , Hidrocortisona/farmacologia , Aprendizagem/efeitos dos fármacos , Dor Nociceptiva/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Dor Visceral/fisiopatologia , Adulto , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Hidrocortisona/análise , Masculino , Dor Nociceptiva/psicologia , Saliva/química , Dor Visceral/psicologia , Adulto Jovem
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