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1.
Braz. J. Pharm. Sci. (Online) ; 58: e18501, 2022. tab, graf
Article in English | LILACS | ID: biblio-1360167

ABSTRACT

Abstract Diabetic Neuropathy (DN) is one of the prevailing micro vascular complications of diabetes which can be characterized by neuropathic pain. Streptozotocin (STZ) induced diabetes in the rat has been increasingly used as a model of painful diabetic neuropathy. STZ injection leads to neurotoxicity of peripheral nerves that leads to development of Peripheral Diabetic Neuropathy in rat model. The present study was aimed at exploring the protective role of Tinospora cordifolia extract in STZ induced neurotoxicity and evaluating mechanisms responsible for attenuating neuropathic pain. Neuropathic pain markers like hyperalgesia, allodynia and motor deficits were assessed before STZ injection and after the treatment with 250 mg/kg and 500 mg/kg dose of Tinospora cordifolia. Oxidative stress markers, NGF expression in sciatic nerve were observed after seven weeks treatment. Our results demonstrated that seven weeks treatment with Tinospora cordifolia leaf extract significantly relieved thermal hyperalgesia and allodynia by increasing the antioxidant enzyme levels, decreasing the lipid peroxidation and by increasing the Nerve growth factor (NGF) expression in diabetic rat sciatic nerves. Our findings highlighted the beneficial effects of oral administration of Tinospora cordifolia extract in attenuating diabetic neuropathic pain, possibly through a strong antioxidant activity and by inducing NGF m RNA in sciatic nerves.


Subject(s)
Animals , Male , Rats , Plants, Medicinal/adverse effects , Plant Extracts/analysis , Menispermaceae/classification , Hyperalgesia/diet therapy
2.
Acta Physiologica Sinica ; (6): 223-232, 2021.
Article in English | WPRIM | ID: wpr-878251

ABSTRACT

The present study was aimed to investigate the role of GluN2B-BDNF pathway in the cerebrospinal fluid-contacting nucleus (CSF-CN) in neuropathic pain. Intra-lateral ventricle injection of cholera toxin subunit B conjugated with horseradish peroxidase (CBHRP) was used to label the CSF-CN. Double-labeled immunofluorescent staining and Western blot were used to observe the expression of GluN2B and BDNF in the CSF-CN. Chronic constriction injury of sciatic nerve (CCI) rat model was used to duplicate the neuropathic pain. Pain behavior was scored to determine the analgesic effects of GluN2B antagonist Ro 25-6981 and BDNF neutralizing antibody on CCI rats. GluN2B and BDNF were expressed in the CSF-CN and their expression was up-regulated in CCI rats. Intra-lateral ventricle injection of GluN2B antagonist Ro 25-6981 or BDNF neutralizing antibody notably alleviated thermal hyperalgesia and mechanical allodynia in CCI rats. Moreover, the increased expression of BDNF protein in CCI rats was reversed by intra-lateral ventricle injection of Ro 25-6981. These results suggest that GluN2B and BDNF are expressed in the CSF-CN and alteration of GluN2B-BDNF pathway in the CSF-CN is involved in the modulation of the peripheral neuropathic pain.


Subject(s)
Animals , Brain-Derived Neurotrophic Factor , Hyperalgesia , Neuralgia , Rats , Rats, Sprague-Dawley , Sciatic Nerve
3.
Article in English | WPRIM | ID: wpr-922103

ABSTRACT

OBJECTIVE@#To investigate the mechanisms underlying elemene-induced analgesia in rats with spared nerve injury (SNI).@*METHODS@#Sixty-five rats were equally divided into 5 groups using a random number table: naive group, sham group, SNI group, SNI + elemene (40 mg·kg@*RESULTS@#The SNI rat model exhibited a significant decrease in paw withdrawal threshold and exploratory behaviour in the EPM (P<0.05). Consecutive administration of elemene alleviated SNI-induced mechanical allodynia and anxiety in rats (P<0.05). Immunohistochemical data showed that elemene decreased SNI-induced upregulation of NDRG2 within the SDH (P<0.05). Double immunofluorescent staining data further showed that elemene decreased SNI-induced upregulation of the number of GFAP immunoreactive (-ir), NDRG-ir, and GFAP/NDRG2 double-labelled cells within the SDH (P<0.05). Immunoblotting data showed that elemene decreased SNI-induced upregulation of GFAP and NDRG2 within the SDH (P<0.05).@*CONCLUSION@#Elemene possibly alleviated neuropathic pain by downregulating the expression of NDRG2 in spinal astrocytes in a rat model of SNI.


Subject(s)
Animals , Astrocytes , Disease Models, Animal , Emulsions , Hyperalgesia/drug therapy , Nerve Tissue Proteins , Neuralgia/drug therapy , Rats , Rats, Sprague-Dawley , Sesquiterpenes , Spinal Cord , Spinal Cord Dorsal Horn
4.
Braz. j. med. biol. res ; 54(10): e11207, 2021. tab, graf
Article in English | LILACS | ID: biblio-1285643

ABSTRACT

Reactive oxygen species (ROS) are involved in neuropathic pain, a complicated condition after nerve tissue lesion. Vitamin D appears to improve symptoms of pain and exhibits antioxidant properties. We investigated the effects of oral administration of vitamin D3, the active form of vitamin D, on nociception, the sciatic functional index (SFI), and spinal cord pro-oxidant and antioxidant markers in rats with chronic constriction injury (CCI) of the sciatic nerve, a model of neuropathic pain. Vitamin D3 (500 IU/kg per day) attenuated the CCI-induced decrease in mechanical withdrawal threshold and thermal withdrawal latency (indicators of antinociception) and SFI. The vitamin prevented increased lipid hydroperoxide levels in injured sciatic nerve without change to total antioxidant capacity (TAC). Vitamin D3 prevented increased lipid hydroperoxide, superoxide anion generation (SAG), and hydrogen peroxide (H2O2) levels in the spinal cord, which were found in rats without treatment at 7 and 28 days post-CCI. A significant negative correlation was found between mechanical threshold and SAG and between mechanical threshold and H2O2 at day 7. Vitamin D3 also prevented decreased spinal cord total thiols content. There was an increase in TAC in the spinal cord of vitamin-treated CCI rats, compared to CCI rats without treatment only at 28 days. No significant changes were found in body weight and blood parameters of hepatic and renal function. These findings demonstrated, for first time, that vitamin D modulated pro-oxidant and antioxidant markers in the spinal cord. Since antinociception occurred in parallel with oxidative changes in the spinal cord, the oxidative changes may have contributed to vitamin D-induced antinociception.


Subject(s)
Animals , Rats , Neuralgia/drug therapy , Antioxidants , Sciatic Nerve , Spinal Cord , Vitamin D , Vitamins , Reactive Oxygen Species , Rats, Wistar , Nociception , Hydrogen Peroxide , Hyperalgesia/drug therapy
5.
SMAD, Rev. eletrônica saúde mental alcool drog ; 16(3): 64-72, jul.-set. 2020. ilus
Article in Portuguese | LILACS, INDEXPSI | ID: biblio-1150192

ABSTRACT

OBJETIVO: analisar parâmetros clínicos sugestivos de sensibilização central em mulheres com disfunção temporomandibular dolorosa crônica antes e após uma intervenção baseada em mindfulness. MÉTODO: onze mulheres com idade entre 27 e 44 anos (36,36 ± 5,61), com diagnóstico de disfunções temporomandibulares dolorosa crônica (Diagnostic Criteria for Temporomandibular Disorders), participaram do estudo. A hiperalgesia, a alodinia e o limiar de dor à pressão foram avaliados em pontos trigeminais e extra-trigeminais antes e após a intervenção baseada em mindfulness, bem como a aplicação do questionário Mindful Attention Awareness Scale. O programa de mindfulness de 8 semanas foi oferecido às participantes do estudo, com base no protocolo Mindfulness Trainings International, em sessões semanais de 2 horas e uma sessão de 4 horas. RESULTADOS: houve redução significativa da alodinia, da hiperalgesia e aumento do limiar de dor à pressão, além de aumento significativo do nível de atenção plena (p < 0,05) enquanto marcador de efetividade da intervenção baseada em mindfulness oferecida. CONCLUSÃO: índices mais saudáveis nos parâmetros clínicos sugestivos de sensibilização central investigados após a intervenção, representam melhora significativa na relação da pessoa com quadro de enfermidade crônica geradora de experiências desagradáveis contínuas como a disfunções temporomandibulares.


OBJECTIVE: manifestations of allodynia and hyperalgesia are commonly present in chronic painful temporomandibular disorder. Studies point to the benefits of people with chronic pain undergoing mindfulness-based interventions, by demonstrating brain, hormonal, and clinical changes. This study aimed to analyze clinical parameters suggestive of central sensitization (pressure pain threshold, allodynia, and hyperalgesia) in women with chronic painful temporomandibular disorder before and after a mindfulness-based intervention, through a before-and-after intervention study, longitudinal, uncontrolled. METHOD: the analysis included 11 women chosen at random from a total of 20, aged between 27 and 44 years (36.36 ± 5.61), diagnosed with chronic painful temporomandibular disorder according to the Diagnostic Criteria for Temporomandibular Disorders protocol and who completed the 8-week mindfulness-based intervention program. Hyperalgesia, allodynia, and pressure pain threshold were tested at trigeminal and extra-trigeminal points before and after the intervention as well as the application of the questionnaire to measure the level of mindfulness (Mindful Attention Awareness Scale). The 8-week mindfulness program was offered to the study participants, based on the Mindfulness Trainings International - protocol, in weekly 2-hour sessions and a 4-hour session (immersion). RESULTS: the results pointed to a reduction in allodynia, hyperalgesia and an increase in pressure pain threshold, with significant differences in several tested points (p <0.05). The changes identified were accompanied by a significant increase in the level of mindfulness (p < 0.05). CONCLUSION: healthier indexes in clinical parameters suggestive of central sensitization investigated after the intervention represent a significant improvement in the person's relationship with a chronic illness that generates continuous unpleasant experiences such as temporomandibular disorder. Thus, the practice of mindfulness represents an appropriate and particularly interesting care because it is a low-cost, non-invasive intervention with low evidence of adverse effects.


OBJETIVO: las manifestaciones de alodinia y hiperalgesia y están comúnmente presentes en lo trastorno temporomandibular doloroso crónico. Los estudios señalan los beneficios de las personas con dolor crónico que se someten a intervenciones basadas en la atención plena, al demostrar cambios cerebrales, hormonales y clínicos. El objetivo de este estudio fue analizar parámetros clínicos sugestivos de sensibilización central (umbral de dolor por presión, alodinia e hiperalgesia) en mujeres con trastorno temporomandibular doloroso crónico antes y después de una intervención basada en la atención plena, a través de un estudio de intervención antes y después, longitudinal, sin control. MÉTODO: el análisis incluyó a 11 mujeres elegidas al azar de un total de 20, con edades entre 27 y 44 años (36.36 ± 5.61), diagnosticadas con trastorno temporomandibular doloroso crónico de acuerdo con protocolo Criterios de diagnóstico para trastornos temporomandibulares y que completaron el 8- programa de intervención basado en mindfulness de una semana. La hiperalgesia, la alodinia y el umbral de dolor por presión se probaron en los puntos trigémino y extra-trigémino antes y después de la intervención, así como también en la aplicación del cuestionario para medir el nivel de atención plena (Escala de conciencia de atención plena). El programa de atención plena de 8 semanas se ofreció a los participantes del estudio, basado en el protocolo Mindfulness Trainings International, en sesiones semanales de 2 horas y una sesión de 4 horas (inmersión). RESULTADOS: los resultados apuntaron a una reducción en la alodinia, hiperalgesia y un aumento en la umbral de dolor por presión, con diferencias significativas en varios puntos probados (p <0.05). Los cambios identificados fueron acompañados por un aumento significativo en el nivel de atención plena (p <0.05), como un marcador de la efectividad de la capacitación ofrecida para la práctica de la atención plena. CONCLUSIÓN: los índices más saludables en los parámetros clínicos sugestivos de sensibilización central investigados después de la intervención, representan una mejora significativa en la relación de la persona con una enfermedad crónica que genera experiencias continuas desagradables como trastorno temporomandibular doloroso crónico. Por lo tanto, la práctica de la atención plena representa una atención aplicable y particularmente interesante porque es una intervención no invasiva de bajo costo con poca evidencia de efectos adversos.


Subject(s)
Humans , Female , Temporomandibular Joint Disorders , Chronic Disease , Surveys and Questionnaires , Pain Threshold , Chronic Pain , Mindfulness , Hyperalgesia
6.
ABCS health sci ; 45: e020016, 02 jun 2020. tab, ilus, graf
Article in English | LILACS | ID: biblio-1123701

ABSTRACT

INTRODUCTION: Different studies have evaluated the effects of electrophysical agents on regeneration after peripheral nerve injury. Among them, the most used in clinical and experimental research is photobiomodulation therapy (PBMT). OBJECTIVE: To analyze the effect of standard energy (16.8 J) of PBMT on peripheral nerve regeneration, applied at different periods after sciatic nerve injury in mice. METHODS: Thirty male Swiss mice were divided into six groups: naive; sham; control; LLLT-01 (660 nm, 16.8 J of total energy emitted in 1 day); LLLT-04 (660 nm, 4.2 J per day, 16.8 J of total energy emitted in 4 days); LLLT-28, (660 nm, 0.6 J per day, 16.8 J of total energy emitted over 28 days). The animals were evaluated using thermal hyperalgesia, Sciatic Functional Index (SFI), and Static Sciatic Index (SSI). Data were obtained at baseline and after 7, 14, 21, and 28 days after surgery. RESULTS: For the SFI and SSI, all groups showed significant differences compared to the control group, and the LLLT-04 group presented the best results among those receiving PBMT. In the assessment of thermal hyperalgesia, there was a significant difference in the 14th day of evaluation in the LLLT-04 group. CONCLUSION: The application of 16.8 J was useful in sciatic nerve regeneration with an improvement of hyperalgesia, with higher efficacy when applied in four days (4.2 J/day).


INTRODUÇÃO: Estudos avaliaram os efeitos de diferentes terapias aplicadas após lesão nervosa periférica, com o intuito de promover a regeneração local. Dentre elas, a mais utilizada em pesquisa clínica e experimental é a terapia de fotobiomodulação (TFBM). OBJETIVO: Analisar o efeito da fotobiomodulação (16,8 J) na regeneração nervosa periférica, aplicada em diferentes regimes após a lesão do nervo ciático em camundongos. MÉTODOS: Foram utilizados trinta camundongos machos (Swiss) divididos em: naive; sham; controle; LBI-01 (660 nm, 16,8 J de energia total emitida em 1 dia); LBI-04 (660 nm, 4,2 J por dia, 16,8 J de energia total emitida em 4 dias); LBI-28, (660 nm, 0,6 J por dia, 16,8 J de energia total emitida durante 28 dias). Os animais foram avaliados utilizando a hiperalgesia térmica, Índice Funcional do Ciático (IFC) e Índice estático do ciático (IEC). Os dados foram obtidos na linha de base e após 7, 14, 21, e 28 dias após a cirurgia. RESULTADOS: Para o IFC e IEC, todos os grupos mostraram um aumento no valor e diferenças significativas em relação ao grupo de controle, e o grupo LBI-04 apresentou os melhores resultados, alcançando valor basal no 21° dia dentre os que foram submetidos a TFBM. Na avaliação da hiperalgesia térmica, houve aumento do tempo de resposta com diferença significativa no 14° dia de avaliação no grupo LBI-04. CONCLUSÃO: A aplicação de 16,8 J foi eficaz na regeneração do nervo ciático quando distribuída ao longo dos 4 primeiros dias pós-lesão, com dose diária de 4,2 J/ponto.


Subject(s)
Animals , Male , Mice , Sciatic Neuropathy/radiotherapy , Low-Level Light Therapy , Nerve Regeneration , Surgical Procedures, Operative , Crush Injuries , Hyperalgesia , Lasers
7.
Braz. j. med. biol. res ; 53(11): e10263, 2020. graf
Article in English | ColecionaSUS, LILACS, ColecionaSUS | ID: biblio-1132488

ABSTRACT

Sensory neuropathy is a dose-limiting side effect of oxaliplatin-based cancer treatment. This study investigated the antinociceptive effect of amifostine and its potential neuroprotective mechanisms on the oxaliplatin-related peripheral sensory neuropathy in mice. Oxaliplatin (1 mg/kg) was injected intravenously in Swiss albino male mice twice a week (total of nine injections), while amifostine (1, 5, 25, 50, and 100 mg/kg) was administered subcutaneously 30 min before oxaliplatin. Mechanical and thermal nociceptive tests were performed once a week for 49 days. Additionally, c-Fos, nitrotyrosine, and activating transcription factor 3 (ATF3) immunoexpressions were assessed in the dorsal root ganglia. In all doses, amifostine prevented the development of mechanical hyperalgesia and thermal allodynia induced by oxaliplatin (P<0.05). Amifostine at the dose of 25 mg/kg provided the best protection (P<0.05). Moreover, amifostine protected against neuronal hyperactivation, nitrosative stress, and neuronal damage in the dorsal root ganglia, detected by the reduced expression of c-Fos, nitrotyrosine, and ATF3 (P<0.05 vs the oxaliplatin-treated group). In conclusion, amifostine reduced the nociception induced by oxaliplatin in mice, suggesting the possible use of amifostine for the management of oxaliplatin-induced peripheral sensory neuropathy.


Subject(s)
Animals , Male , Rabbits , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/prevention & control , Amifostine/therapeutic use , Oxaliplatin , Hyperalgesia/chemically induced , Hyperalgesia/prevention & control , Hyperalgesia/drug therapy , Antineoplastic Agents/toxicity
8.
Article in English | WPRIM | ID: wpr-782067

ABSTRACT

3) of the pain in domains of tingling/prickling sensation (p=0.024), mechanical allodynia (p=0.027), sudden pain attacks (p=0.018), and thermal hyperalgesia (p=0.002) were significantly more frequent in NMOSD compared to MS patients. Among the patients experiencing pain with a neuropathic component, total pain-related interference (p=0.045) scores were significantly higher in NMOSD patients than in MS patients. In daily life, pain interfered with normal work (p=0.045) and relationships with other people (p=0.039) more often in NMOSD patients than in MS patients. Although pain medication was prescribed more frequently in NMOSD patients, the percentage of patients experiencing medication-related pain relief was lower in those patients.CONCLUSIONS: The severity of neuropathic pain and the pain-related interference in daily life were greater in NMOSD patients than in MS patients. Individualized analgesic management should be considered based on a comprehensive understanding of neuropathic pain in these patients.


Subject(s)
Humans , Hyperalgesia , Korea , Multiple Sclerosis , Neuralgia , Neuromyelitis Optica , Referral and Consultation , Sensation , Sex Ratio
9.
Article in Chinese | WPRIM | ID: wpr-880794

ABSTRACT

OBJECTIVE@#To investigate the effect of escin in relieving chemotherapy-induced peripheral neuropathic pain in rats and explore and the underlying mechanism.@*METHODS@#Eighteen SD rats were randomly divided into 3 groups (@*RESULTS@#The rats in both the escin preconditioning group and escin postconditioning group showed obviously increased thresholds of mechanical allodynia and thermal hyperalgesia as compared with those in the control group (@*CONCLUSIONS@#Escin can alleviate chemotherapy-induced peripheral neuropathic pain in rats possibly by upregulating the expressions of autophagy-related proteins in the spinal cord.


Subject(s)
Animals , Antineoplastic Agents/therapeutic use , Autophagy , Escin/therapeutic use , Hyperalgesia/drug therapy , Mice , Neuralgia/drug therapy , Rats , Rats, Sprague-Dawley , Spinal Cord
10.
Biol. Res ; 53: 36, 2020. tab, graf
Article in English | LILACS | ID: biblio-1131882

ABSTRACT

BACKGROUND: To investigate the thalamic neurotransmitters and functional connections in the development of chronic constriction injury (CCI)-induced neuropathic pain. METHODS: The paw withdrawal threshold was measured by mechanical stimulation the right hind paw with the von frey hair in the rats of CCI-induced neuropathic pain. The N-acetylaspartate (NAA) and Glutamate (Glu) in thalamus were detected by magnetic resonance spectrum (MRS) process. The thalamic functional connectivity with other brain regions was scanned by functional magnetic resonance image (fMRI). RESULTS: The paw withdrawal threshold of the ipsilateral side showed a noticeable decline during the pathological process. Increased concentrations of Glu and decreased levels of NAA in the thalamus were significantly correlated with mechanical allodynia in the neuropathic pain states. The thalamic regional homogeneity (ReHo) decreased during the process of neuropathic pain. The functional connectivity among the thalamus with the insula and somatosensory cortex were significantly increased at different time points (7, 14, 21 days) after CCI surgery. CONCLUSION: Our study suggests that dynamic changes in thalamic NAA and Glu levels contribute to the thalamic functional connection hyper-excitation during CCI-induced neuropathic pain. Enhanced thalamus-insula functional connection might have a significant effect on the occurrence of neuropathic pain.


Subject(s)
Animals , Rats , Thalamus/metabolism , Wounds and Injuries/physiopathology , Neurotransmitter Agents/metabolism , Neuralgia , Thalamus/physiopathology , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Glutamic Acid/metabolism , Constriction , Hyperalgesia
11.
Experimental Neurobiology ; : 679-696, 2019.
Article in English | WPRIM | ID: wpr-785789

ABSTRACT

Spinal cord injury (SCI) causes axonal damage and demyelination, neural cell death, and comprehensive tissue loss, resulting in devastating neurological dysfunction. Neural stem/progenitor cell (NSPCs) transplantation provides therapeutic benefits for neural repair in SCI, and glial cell line-derived neurotrophic factor (GDNF) has been uncovered to have capability of stimulating axonal regeneration and remyelination after SCI. In this study, to evaluate whether GDNF would augment therapeutic effects of NSPCs for SCI, GDNF-encoding or mock adenoviral vector-transduced human NSPCs (GDNF-or Mock-hNSPCs) were transplanted into the injured thoracic spinal cords of rats at 7 days after SCI. Grafted GDNF-hNSPCs showed robust engraftment, long-term survival, an extensive distribution, and increased differentiation into neurons and oligodendroglial cells. Compared with Mock-hNSPC- and vehicle-injected groups, transplantation of GDNF-hNSPCs significantly reduced lesion volume and glial scar formation, promoted neurite outgrowth, axonal regeneration and myelination, increased Schwann cell migration that contributed to the myelin repair, and improved locomotor recovery. In addition, tract tracing demonstrated that transplantation of GDNF-hNSPCs reduced significantly axonal dieback of the dorsal corticospinal tract (dCST), and increased the levels of dCST collaterals, propriospinal neurons (PSNs), and contacts between dCST collaterals and PSNs in the cervical enlargement over that of the controls. Finally grafted GDNF-hNSPCs substantially reversed the increased expression of voltage-gated sodium channels and neuropeptide Y, and elevated expression of GABA in the injured spinal cord, which are involved in the attenuation of neuropathic pain after SCI. These findings suggest that implantation of GDNF-hNSPCs enhances therapeutic efficiency of hNSPCs-based cell therapy for SCI.


Subject(s)
Animals , Axons , Cell Death , Cell Movement , Cell- and Tissue-Based Therapy , Cicatrix , Demyelinating Diseases , gamma-Aminobutyric Acid , Glial Cell Line-Derived Neurotrophic Factor , Humans , Hyperalgesia , Myelin Sheath , Neuralgia , Neurites , Neuroglia , Neurons , Neuropeptide Y , Paraplegia , Pyramidal Tracts , Rats , Regeneration , Spinal Cord Injuries , Spinal Cord , Therapeutic Uses , Transplants , Voltage-Gated Sodium Channels
12.
Article in Chinese | WPRIM | ID: wpr-776524

ABSTRACT

OBJECTIVE@#To investigate the effects of ginsenoside-Rg on mechanical allodynia, heat hyperalgeia, depressive state of rats with chronic sciatic nerve constriction injury.@*METHODS@#Fifty SD rats were randomly divided into 5 groups: blank control group (Normal, normal + saline),sham operation group (Sham, sham operation + saline),chronic constriction injury of the sciatic nerve group (CCI, CCI + saline),ginsenoside-Rg low dose group (CCI + Rg 5 mg/kg), and ginsenoside-Rg high dose group (CCI + Rg 10 mg/kg).After the CCI model was established,drug were injected into the abdominal cavity through the syringe once a day,for 14 consecutive days.The mechanical shrinkage foot reflex threshold (MWT) and thermal withdrawal latency(TWL) were determined at 1 d before the operation and at 1,3,5,7,10 and 14 d after the operation.Light-dark transition test, forced swimming test were determined at 1 d before the operation and at 14 d after the operation.@*RESULTS@#Compared with the sham group, the MWL and TWL of the CCI rats were decreased significantly (P<0.01), time in the light compartment and number of transition were decreased (P<0.01), the immobility time in FST was also prolonged significantly (P<0.01). At 14 days after CCI operation, the MWL and TWL of the ginsenoside-Rg groups were increased significantly (P<0.01), time in the light compartment and number of transition were also shortened significantly (P<0.01), the immobility time in FST was also shortened significantly (P<0.01).@*CONCLUSION@#Intraperitoneal injection of ginsenoside-Rg can inhibit the mechanical and thermal pain sensitivity of CCI rats,and can relieve depressive state.


Subject(s)
Animals , Constriction , Ginsenosides , Pharmacology , Hot Temperature , Hyperalgesia , Drug Therapy , Random Allocation , Rats , Rats, Sprague-Dawley , Sciatic Nerve , Wounds and Injuries
13.
Article in Chinese | WPRIM | ID: wpr-776036

ABSTRACT

Objective To investigate the effects of simvastatin on diabetic neuropathic pain and systematic inflammation in diabetic rats and explore their molecular mechanisms.Methods Totally 24 rats were equally randomized into the normal+vehicle(NV)group,diabetic+vehicle(DV)group,and diabetic+simvastatin(DS)group using the random number table.Streptozotocin(STZ)was used to establish the rat models of diabetes.Blood glucose,body mass,paw withdrawal mechanical threshold(PWMT),and paw withdrawal thermal latency(PWTL)in each group were observed on days 7,14,21,and 28 after STZ injection.On day 28 after STZ injection,rats were sacrificed,and the lumbar spinal dorsal horn and serum were collected.Western blotting was used to detect the expression of receptor for advanced glycation end products(RAGE)and the phosphorylation levels of protein kinase B(AKT),extracellular signal-regulated kinase(ERK),p38,and c-Jun N-terminal kinase(JNK)in the spinal dorsal horn of rats in each group.Enzyme-linked immunosorbent assay was performed to determine the serum concentrations of oxidized low density lipoprotein(ox-LDL)and interleukin-1β(IL-1β).Results On days 14,21 and 28 after STZ injection,the PWMT in DV group were(8.6 ± 0.8),(7.1 ± 1.6),and(7.8 ± 0.8)g respectively,which were significantly lower than (12.0 ± 0.9)(=8.482, =0.000),(11.6 ± 1.5)(=11.309, =0.000),and(11.7 ± 1.5)g(=9.801, =0.000)in NV group.The PWMT in DS group on days 21 and 28 were(9.4 ± 1.4)(=5.780, =0.000)and(9.7 ± 0.9)g(=4.775, =0.003),respectively,which were significantly improved comparing with those of DV group.On days 7,14,21,and 28,there were no significant differences in PWTL among these three groups (all <0.05).The expression of RAGE in the spinal dorsal horn of DV group was significantly higher than those of NV group(=6.299, =0.000)and DS group(=2.891, =0.025).The phosphorylation level of AKT in the spinal dorsal horn of DV group was significantly higher than those of NV group(=8.915,=0.000)and DS group(=4.103,=0.003).The phosphorylation levels of ERK( =8.313,=0.000),p38( =2.965, =0.022),and JNK(=7.459, =0.000)in the spinal dorsal horn of DV group were significantly higher than those of NV group;the phosphorylation level of JNK in the spinal dorsal horn of DS group was significant lower than that of DV group(=3.866, =0.004);however,there were no significant differences in the phosphorylation levels of ERK(=1.987,=0.122)and p38(=1.260,=0.375)in the spinal dorsal horn between DS group and DV group.The serum concentrations of ox-LDL and IL-1β in DV group were(41.86 ± 13.40)ng/ml and(108.16 ± 25.88)pg/ml,respectively,which were significantly higher than those in NV group [(24.66 ± 7.87)ng/ml(=3.606,=0.003)and(49.32 ± 28.35)pg/ml(=5.079,=0.000)] and DS group [(18.81 ± 5.62)ng/ml (=4.833, =0.000)and(32.73 ± 11.73)pg/ml(=6.510, =0.000)].Conclusions Simvastatin can relieve the mechanical allodynia of diabetic rats possibly by inhibiting the activation of RAGE/AKT and the phosphorylation of JNK in the spinal dorsal horn.Simvastatin can also decrease the serum concentrations of ox-LDL and IL-1β in diabetic rats,which may contribute to the relief of systematic inflammation.


Subject(s)
Animals , Diabetes Mellitus, Experimental , Hyperalgesia , Inflammation , Drug Therapy , Interleukin-1beta , Blood , Lipoproteins, LDL , Blood , Neuralgia , Drug Therapy , Proto-Oncogene Proteins c-akt , Metabolism , Random Allocation , Rats , Rats, Sprague-Dawley , Receptor for Advanced Glycation End Products , Metabolism , Simvastatin , Pharmacology
14.
Neuroscience Bulletin ; (6): 301-314, 2019.
Article in English | WPRIM | ID: wpr-775476

ABSTRACT

Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brush-evoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1 (Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury (SNI). Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in naïve but also in ML133-pretreated mice. In contrast, bicuculline, a GABA receptor antagonist, induced only punctate, but not dynamic, allodynia. These results indicated the involvement of glycinergic transmission in the development of dynamic allodynia. We further found that SNI significantly suppressed the frequency, but not the amplitude, of the glycinergic spontaneous inhibitory postsynaptic currents (gly-sIPSCs) in neurons on the lamina II-III border of the spinal dorsal horn, and pretreatment with ML133 prevented the SNI-induced gly-sIPSC reduction. Furthermore, 5 days after SNI, ML133, either by intrathecal administration or acute bath perfusion, and strychnine sensitively reversed the SNI-induced dynamic, but not punctate, allodynia and the gly-sIPSC reduction in lamina IIi neurons, respectively. In conclusion, our results suggest that blockade of Kir2.1 channels in the spinal dorsal horn selectively inhibits dynamic, but not punctate, mechanical allodynia by enhancing glycinergic inhibitory transmission.


Subject(s)
Animals , Bicuculline , Pharmacology , Disease Models, Animal , Glycine , Metabolism , Hyperalgesia , Drug Therapy , Metabolism , Imidazoles , Pharmacology , Inhibitory Postsynaptic Potentials , Physiology , Male , Mice, Inbred C57BL , Neurons , Metabolism , Neurotransmitter Agents , Pharmacology , Peripheral Nerve Injuries , Drug Therapy , Metabolism , Phenanthrolines , Pharmacology , Potassium Channels, Inwardly Rectifying , Metabolism , Receptors, GABA-A , Metabolism , Receptors, Glycine , Metabolism , Strychnine , Pharmacology , Synaptic Transmission , Physiology , Tissue Culture Techniques , Touch
15.
Neuroscience Bulletin ; (6): 4-14, 2019.
Article in English | WPRIM | ID: wpr-775443

ABSTRACT

The pathophysiology of visceral pain in patients with irritable bowel syndrome remains largely unknown. Our previous study showed that neonatal maternal deprivation (NMD) does not induce visceral hypersensitivity at the age of 6 weeks in rats. The aim of this study was to determine whether NMD followed by adult stress at the age of 6 weeks induces visceral pain in rats and to investigate the roles of adrenergic signaling in visceral pain. Here we showed that NMD rats exhibited visceral hypersensitivity 6 h and 24 h after the termination of adult multiple stressors (AMSs). The plasma level of norepinephrine was significantly increased in NMD rats after AMSs. Whole-cell patch-clamp recording showed that the excitability of dorsal root ganglion (DRG) neurons from NMD rats with AMSs was remarkably increased. The expression of β adrenergic receptors at the protein and mRNA levels was markedly higher in NMD rats with AMSs than in rats with NMD alone. Inhibition of β adrenergic receptors with propranolol or butoxamine enhanced the colorectal distention threshold and application of butoxamine also reversed the enhanced hypersensitivity of DRG neurons. Overall, our data demonstrate that AMS induces visceral hypersensitivity in NMD rats, in part due to enhanced NE-β adrenergic signaling in DRGs.


Subject(s)
Adrenergic Agents , Pharmacology , Animals , Ganglia, Spinal , Hyperalgesia , Drug Therapy , Hypersensitivity , Drug Therapy , Male , Maternal Deprivation , Neurons , Patch-Clamp Techniques , Methods , Rats, Sprague-Dawley , Signal Transduction , Stress, Physiological , Physiology , Visceral Pain , Metabolism
16.
Article in Chinese | WPRIM | ID: wpr-813294

ABSTRACT

To investigate the role of metabotropic glutamate receptor 5 (mGluR5) in laterocapcular division of the central nucleus of amygdala (CeLC) in fentanyl-induced hyperalgesia in rats. 
 Methods: A total of 12 Sprague-Dawley male rats (60-100 g) were randomly divided into a normal group 1 (n=6) and an opioid-induced hyperalgesia (OIH) group 1 (n=6). The OIH group 1 was injected with fentanyl through the lower neck skin to build OIH model, and the normal group 1 was given the same volume of saline. After 6.5 h, paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were tested to verify the success of the induction of OIH. Then rats were sacrificed and the right CeLC tissue were taken for detection of the mGluR5 by Western blotting. Forty SD male rats were randomly divided into 4 groups (n=10 each): an OIH+DMSO, an OIH+MTEP (3.0 μg), an OIH+MTEP (7.5 μg) and an OIH+MTEP (15.0 μg) group. MTEP was a selective antagonist of mGluR5. Catheterization in the right CeLC was first performed. After one-week recovery, OIH was induced. Then 0.5 μL DMSO, MTEP 3.0 μg, MTEP 7.5 μg and MTEP 15.0 μg were administrated through the CeLC catheter accordingly. PWMT and PWTL were tested at pre-OIH, 6 h after OIH and post-drug. Then the expression levels of mGluR5 of CeLC tissue were analyzed by Western blotting. Another 8 SD male rats were randomly divided into a normal group 2 and an OIH group 2 (n=4 each). The rats were induced OIH by injecting of fentanyl while rats in the normal group 2 were injected with same volume of saline. The miniature excitatory postsynaptic currents (mEPSCs) of the 2 groups' neurons in the right CeLC region were recorded by whole cell voltage-clamp before and after the administration of MTEP in brain slice.
 Results: Compared with the normal group 1, the PWTL and PWMT were significantly decreased and the expression of mGluR5 was apparently increased in the OIH group 1 (P<0.05). The PWMT and PWTL were significantly decreased in each group and indicated success of OIH model (P<0.05). The expression of mGluR5 in the CeLC was increased. MTEP reversed these changes in a dose-dependent way (P<0.05). Compared with the normal group 2, the amplitude and frequency of mEPSCs in the OIH group 2 were significantly increased (P<0.05) and they were reversed by MTEP (P<0.05). 
 Conclusion: mGluR5 in the CeLC may be involved in the maintenance of OIH. Inhibition of the activity of mGluR5 in the CeLC may alleviate the symptoms of fentanyl-induced hyperalgesia.


Subject(s)
Animals , Central Amygdaloid Nucleus , Fentanyl , Hyperalgesia , Male , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5
17.
Article in Chinese | WPRIM | ID: wpr-813293

ABSTRACT

To explore the role of P2X4 receptor in opioid-induced hyperalgesia (OIH).
 Methods: A total of 30 Sprague-Dawley (SD) male rats were randomly divided into 5 groups: a saline (N0) group, a remifentanil at 0.5 μg/(kg.min) (R1) group, a remifentanil at 1.0 μg/(kg.min) (R2) group, a remifentanil at 1.5 μg/(kg.min) (R3) group, and a remifentanil at 5.0 μg/(kg.min) (R4) group. The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured at follow time points to optimize the dosages: the day before treatment (T1), 30 min after tail intravenous catheterization (T2), and 30 min (T3), 1 h (T4), 2 h (T5), 24 h (T6) after withdrawal from remifentanil. Then, the rats were randomly divided into 2 groups: a saline group (N group), a remifentanil at 1.0 μg/(kg.min) group (R group). The PWMT and PWTL were measured at follow time points: T1, T2, and T4. The lumbar enlargement of spine was selected at 1 h after withdrawal from remifentanil, and the expression of P2X4 receptor mRNA and protein was examined in OIH. Additional male rats were selected and randomly divided into 2 groups: a plantar incision surgery followed by saline treatment group (I+N group), a plantar incision surgery followed by remifentanil treatment group (I+R group). The PWMT and PWTL were measured at follow time points: T1, T2, T3, T4, T5, T6, 48 h (T7) and 72 h (T8) after withdrawal from remifentanil. The lumbar enlargement of spine was selected at 1 h after withdrawal from remifentanil, the expression of P2X4 receptor mRNA and protein was examined by PCR and Western blotting, and the microglial activation in spine 1 h after withdrawal from remifentanil were assessed by immunofluorescence.
 Results: The pain thresholds including PWMT and PWTL in different groups were as follows: R4 group

Subject(s)
Animals , Hyperalgesia , Male , Pain, Postoperative , Rats , Rats, Sprague-Dawley , Receptors, Purinergic P2X4 , Remifentanil , Spinal Cord
18.
Article in Chinese | WPRIM | ID: wpr-813292

ABSTRACT

To investigate whether mammalian target of rapamycin (mTOR) signaling pathway is involved in peripheral nerve injury-induced hyperalgesia through activation of spinal dorsal astrocytes in rats.
 Methods: A total of 30 male Sprague-Dawley (SD) rats were randomly divided into 6 groups (n=5): the 1 day group (D1 group), the 4 days group (D4 group), the 7 days group (D7 group), the 14 days group (D14 group), the normal group and the sham group. The sciatic nerve chronic constriction injury (CCI) model was established in the D1, D4, D7 and D14 group. The normal group received no treatment while the sham group was only exposed the sciatic nerve. Paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured at the 1st, 4th, 7th, and 14th day after CCI in the different groups. Lumbar spinal cord were harvested on the 1st, 4th, 7th and 14th day in the D1, D4, D7, D14 group correspondingly, which were harvested on the 14th day in the normal group and the sham group. Distribution of mTOR in rat spinal cord was assessed by immunohistochemistry. The expressions of mTOR mRNA and protein in the spinal cord in different groups were determined by real-time PCR and Western blotting, respectively. Another 30 male intrathecal catheterized SD rats were randomly divided into 6 groups (n=5): a blank group, a CCI group, a CCI+early rapamycin (RAPA) group, a CCI+early dimethylsulfoxide (DMSO) group, a CCI+ later RAPA group, and a CCI+later DMSO group. The blank group didn't received any treatment; The CCI group was carried out the treatment of CCI model in the left hind limbs. 10 μL of 1% RAPA was given to the CCI+early RAPA group intrathecally at 4 hours after CCI for 3 days; the CCI+later RAPA group were treated with the same dose of RAPA on the 7th days after CCI for 3 days; the CCI+early DMSO group and the CCI+later DMSO group were injected with the same volume of 4% DMSO at the corresponding time as controls. The PWTL and PWMT were measured before and after intrathecal catheterization, and every other day after CCI. The lumbar spinal cords were selected and the expression of glial fibrillary acidic protein (GFAP) in spinal dorsal horn were examined by immunohistochemistry in the 14th day after CCI.
 Results: The immunohistochemistry positive particles of mTOR were widely distributed in the cytoplasm of the normal spinal neurons. Compared with the base line, the PWMT in the D14 group on the 1st, 4th, 7th and 14th day after CCI were significantly lower, and the PWTL on the 4th, 7th and 14th day after CCI were also significantly lower (P<0.05 or P<0.01). The expressions of mTOR mRNA and protein in the CCI groups (D1, D4, D7 and D14 group) were significantly increased than those in the normal group (P<0.05 or P<0.01). Compared with the CCI+early DMSO group, the PWMT and PWTL in the CCI+early RAPA group were obviously increased on 4th, 6th, 8th, 10th, 12th or 14th day after CCI (P<0.05 or P<0.01); compared with the CCI+later DMSO group, the PWMT and PWTL in the CCI+later RAPA group were also significantly increased at the 8th, 10th or 14th day after CCI (P<0.01 or P<0.05). The GFAP immunohistochemistry positive area and absorbance value in the dorsal horn of the lumbar spinal cord in the CCI rats were decreased in the CCI+early RAPA group compared with the CCI+early DMSO group (P<0.05 or P<0.01), and which were also decreased in the CCI+later RAPA group compared with the CCI+later DMSO group (P<0.05 or P<0.01).
 Conclusion: mTOR signaling pathway may be involved in hyperalgesia induced by peripheral nerve injury via spinal astrocyte activation in the dorsal horn of the spinal cord.


Subject(s)
Animals , Hyperalgesia , Male , Neuralgia , Peripheral Nerve Injuries , Rats , Rats, Sprague-Dawley , Signal Transduction , Spinal Cord , TOR Serine-Threonine Kinases
19.
Article in English | WPRIM | ID: wpr-759498

ABSTRACT

BACKGROUND: The pain-relief properties of tricyclic antidepressants can be attributed to several actions. Recent observations suggest that adenosine is involved in the antinociceptive effect of amitriptyline. The A3 adenosine receptor (A3AR) is the only adenosine subtype overexpressed in inflammatory and cancer cells. This study was performed to investigate the role of A3AR in the anti-nociceptive effect of amitriptyline. METHODS: Spinal nerve-ligated neuropathic pain was induced by ligating the L5 and L6 spinal nerves of male Sprague-Dawley rats. The neuropathic rats were randomly assigned to one of the following three groups (8 per group): a neuropathic pain with normal saline group, a neuropathic pain with amitriptyline group, and a neuropathic pain with amitriptyline and 3-ethyl-5-benzyl- 2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS) group. Amitriptyline or saline was administered intraperitoneally and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191), an A3AR antagonist, was injected subcutaneously immediately before amitriptyline administration. The level of extracellular signal-regulated kinase P44/42 (ERK1/2), cyclic AMP response element-binding protein (CREB), and proinflammatory cytokines were assessed using immunoblotting or reverse-transciption polymerase chain reaction. RESULTS: Amitriptyline increased the mechanical withdrawal threshold of the neuropathic rats. The level of phospho-ERK1/2 and phospho-CREB proteins, and proinflammatory cytokines produced by spinal nerve ligation were significantly reduced by amitriptyline administration. However, the use of MRS-1191 before amitriptyline administration not only reduced the threshold of mechanical allodynia, but also increased the signaling protein and proinflammatory cytokine levels, which were reduced by amitriptyline. CONCLUSIONS: The results of this study suggest that the anti-nociceptive effect of amitriptyline involves the suppression of ERK1/2 and CREB signaling proteins, and A3AR activation also affects the alleviation of the inflammatory response.


Subject(s)
Adenosine , Amitriptyline , Animals , Antidepressive Agents, Tricyclic , Cyclic AMP Response Element-Binding Protein , Cytokines , Humans , Hyperalgesia , Immunoblotting , Ligation , Male , Neuralgia , Phosphotransferases , Polymerase Chain Reaction , Rats , Rats, Sprague-Dawley , Receptors, Purinergic P1 , Spinal Nerves
20.
Article in Chinese | WPRIM | ID: wpr-773512

ABSTRACT

OBJECTIVE@#To investigate the role of zinc-fingers and homeoboxes 2 (ZHX2) in regulating μ-opioid receptor expression in the dorsal root ganglion (DRG) in mice with peripheral nerve injury-induced pain hypersensitivity.@*METHODS@#Forty-eight male adult C57BL6J mice were randomized into 4 groups and subjected to chronic constriction injury (CCI) of the sciatic nerve or sham operation followed by microinjection of a specific small interfering RNA (siRNA) of ZHX2 or a negative control siRNA sequence (siNC) into the DRG. Seven days later, the mice were examined for changes in the hind paw withdrawal frequency (PWF), after which the DRG tissue was collected for detecting the expressions of μ-opioid receptor at the mRNA and protein levels using RT-qPCR and Western blotting. In another experiment, the DRG tissues were collected from 6 mice (21-day-old) for primary culture of the DRG neurons, which were transfected with ZHX2 siRNA or the siNC to observe the changes in the expressions of ZHX2 and μ-pioid receptor.@*RESULTS@#Microinjection of ZHX2 siRNA into the ipsilateral L3 and L4 DRGs significantly reversed CCI-induced μ-pioid receptor downregulation in the injured DRG and alleviated CCI-induced mechanical allodynia in the mice. In the cell experiment, ZHX2 knockdown obviously upregulated the mRNA and protein expressions of opioid receptor in the primary cultured DRG neurons.@*CONCLUSIONS@#ZHX2 knockdown in the DRG reverses CCI-induced down-regulation of μ opioid receptor to alleviate periphery nerve injury-induced pain hypersensitivity in mice.


Subject(s)
Animals , Ganglia, Spinal , Homeodomain Proteins , Hyperalgesia , Male , Mice , Neuralgia , Rats, Sprague-Dawley , Receptors, Opioid, mu
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