RESUMO
BACKGROUND: Human immunodeficiency virus (HIV)-associated distal symmetric peripheral neuropathy (DSPN) is one of the most frequent neurological complications of HIV infection, and causes pain and dysaesthesias in millions globally. Many individuals with this infection report using acupuncture to manage their symptoms, but evidence supporting the use of acupuncture is limited. This systematic review will assess the effectiveness and safety of acupuncture for patients with HIV-associated DSPN. METHODS: Databases including MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Scopus, Web of science, AMED (Allied and Complementary Medicine), the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, Wanfang Database, VIP Database and clinical trials registers (the WHO International Clinical Trials Registry Platform portal and www.ClinicalTrials.gov) will be electronically searched from inception to December 1, 2020. All randomized controlled trials in English or Chinese without restriction on publication status will be included. Selection of studies, extraction of data, and assessment of studies quality will be independently performed by 2 reviewers. The primary outcome measure will be the change in pain intensity assessed by validated scales. Secondary outcomes include change in neurologic summary scores, quality of life, physical function evaluated by admitted tools, and adverse events related to acupuncture reported in the included trials. If possible, a meta-analysis will be conducted to provide an estimate of the pooled treatment effect using Review Manager 5.3 statistical software. Otherwise, qualitative descriptive analysis will be given. The results will be presented as the risk ratio for binary data and the mean difference (MD) or standardized MD for continuous data. RESULTS: The results of the systematic review will be disseminated via publication in a peer-reviewed journal and presented at a relevant conference. CONCLUSION: This review will be the first review entirely focused on assessing the effectiveness and safety of acupuncture for HIV-associated DSPN. PROSPERO REGISTRATION NUMBER: CRD42020210994.
Assuntos
Terapia por Acupuntura/efeitos adversos , Infecções por HIV/complicações , Neuralgia/terapia , Parestesia/terapia , Polineuropatias/terapia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Metanálise como Assunto , Neuralgia/diagnóstico , Neuralgia/imunologia , Neuralgia/virologia , Medição da Dor , Parestesia/diagnóstico , Parestesia/imunologia , Parestesia/virologia , Polineuropatias/diagnóstico , Polineuropatias/imunologia , Polineuropatias/virologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Revisões Sistemáticas como Assunto , Resultado do TratamentoRESUMO
Mutations within the SCN11A gene which encodes the voltage-gated sodium channel NaV1.9 mainly expressed in small fiber sensory neurons have been associated with neuropathic disorders; however, suitable medications have not been fully investigated. To develop drug therapies against NaV1.9-related neuropathic pain, we aimed to establish a novel model using mice carrying the Scn11a p.R222S mutation initially identified in patients with familial episodic limb pain that is characterized by paroxysmal pain induced by fatigue or bad weather conditions. We investigated the influence of cold exposure (4 °C, overnight) on the behavioral and biochemical phenotypes of Scn11a p.R222S mutant (R222S) and wild type C57BL/6N (WT) mice. We also tested the effects of acetaminophen (125, 250 mg/kg, perorally, p.o.) and traditional Japanese medicine, goshajinkigan (0.5 or 1.0 g/kg, p.o.), which are analgesic drugs prescribed to patients with neuropathic pain, in this model of cold-induced mechanical allodynia in R222S mice.Cold-exposed R222S mice exhibited enhanced mechanical allodynia and thermal hypersensitivity compared with WT mice. The decrease of the mechanical withdrawal threshold in R222S mice was reversible 24 h after housing at room temperature. There was no significant change in the levels of interleukin-1ß, interleukin-6, tumor necrosis factor-α, or interferon-γ in the plasma or spinal cords of WT and R222S mice after cold exposure. Both acetaminophen (250 mg/kg) and goshajinkigan (1.0 g/kg) significantly attenuated mechanical allodynia in R222S mice. The model of cold-induced mechanical allodynia in mice with the Scn11a p.R222S mutation is novel and useful for evaluating analgesic drugs for intractable neuropathies related to NaV1.9.
Assuntos
Modelos Animais de Doenças , Hiperalgesia , Canal de Sódio Disparado por Voltagem NAV1.9/genética , Neuralgia , Acetaminofen/uso terapêutico , Analgésicos/uso terapêutico , Animais , Temperatura Baixa , Citocinas/sangue , Citocinas/imunologia , Medicamentos de Ervas Chinesas/uso terapêutico , Membro Posterior/patologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/genética , Hiperalgesia/imunologia , Hiperalgesia/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação de Sentido Incorreto , Neuralgia/tratamento farmacológico , Neuralgia/genética , Neuralgia/imunologia , Neuralgia/patologia , Medula Espinal/imunologia , TatoRESUMO
Acupuncture therapy is performed by applying the needle insertion at discrete cutaneous locations and used for the treatments of diverse symptoms and disorders. In order to elucidate mechanistic basis on how acupuncture stimulation (AS) produces therapeutic effects, it is primarily important to understand tissue responses locally at the acupuncture site (acupoint). Here, we investigated integrin protein as molecular target responding to and integrating AS. Signals of α6 and ß1 integrins were clearly induced at zusanli acupoint 24 h after AS in areas of nuclear clusters around the needle track. Induction levels of integrin were largely reduced by needle insertion at non-acupuncture point or without needle rotation. Phospho-Erk1/2 was initially decreased below the basal level after AS but increased 24 h later. Induction pattern of phospho-Erk1/2 was as similar as that of α6 integrin in its selectivity to needling procedure and tissue distribution. We further found that mRNA expression of P2X3 purinergic receptor was upregulated in the dorsal root ganglion (DRG) after AS, but decreased by the inhibition of Erk1/2 activity at the acupuncture area. Moreover, AS-mediated integrin activation was required for Erk1/2 activation at the acupuncture site and regulation of pain sensitivity in the hind paw. The present results provide a new evidence on acupuncture-specific tissue response in terms of integrin induction, and further suggest that integrin activation may be involved in transmitting mechanosensory signals from the acupoint to afferent nerve fiber.
Assuntos
Terapia por Acupuntura/métodos , Integrina alfa6/imunologia , Integrina beta1/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Neuralgia/imunologia , Neuralgia/terapia , Pontos de Acupuntura , Animais , Masculino , Mecanotransdução Celular/imunologia , Neuralgia/diagnóstico , Estimulação Física/métodos , Ratos , Ratos Sprague-Dawley , Resultado do TratamentoRESUMO
BACKGROUND: Oxaliplatin, a widely used anticancer drug against metastatic colorectal cancer, can induce acute peripheral neuropathy, which is characterized by cold and mechanical allodynia. Activation of glial cells (e.g. astrocytes and microglia) and increase of pro-inflammatory cytokines (e.g. IL-1ß and TNF-α) in the spinal cord play a crucial role in the pathogenesis of neuropathic pain. Our previous study demonstrated that Gyejigachulbu-Tang (GBT), a herbal complex formula, alleviates oxaliplatin-induced neuropathic pain in rats by suppressing spinal glial activation. However, it remains to be elucidated whether and how Buja (Aconiti Tuber), a major ingredient of GBT, is involved in the efficacy of GBT. METHODS: Cold and mechanical allodynia induced by an oxaliplatin injection (6 mg/kg, i.p.) in Sprauge-Dawley rats were evaluated by a tail immersion test in cold water (4 °C) and a von Frey hair test, respectively. Buja (300 mg/kg) was orally administrated for five consecutive days after the oxaliplatin injection. Glial activation in the spinal cord was quantified by immunohistochemical staining using GFAP (for astrocytes) and Iba-1 (for microglia) antibodies. The amount of spinal pro-inflammatory cytokines, IL-1ß and TNF-α, were measured by ELISA. RESULTS: Significant behavioral signs of cold and mechanical allodynia were observed 3 days after an oxaliplatin injection. Oral administration of Buja significantly alleviated oxaliplatin-induced cold and mechanical allodynia by increasing the tail withdrawal latency to cold stimuli and mechanical threshold. Immunohistochemical analysis showed the activation of astrocytes and microglia and the increase of the IL-1ß and TNF-α levels in the spinal cord after an oxaliplatin injection. Administration of Buja suppressed the activation of spinal astrocytes without affecting microglial activation and down-regulated both IL-1ß and TNF-α levels in the spinal cord. CONCLUSIONS: Our results indicate that Buja has a potent anti-allodynic effect in a rat model of oxaliplatin-induced neuropathic pain, which is associated with the inhibition of activation of astrocytes and release of pro-inflammatory cytokines in the spinal cord. Thus, our findings suggest that administration of Buja could be an alternative therapeutic option for the management of peripheral neuropathy, a common side-effect of oxaliplatin.
Assuntos
Antineoplásicos/efeitos adversos , Astrócitos/efeitos dos fármacos , Citocinas/genética , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Compostos Organoplatínicos/efeitos adversos , Animais , Astrócitos/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/genética , Hiperalgesia/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Masculino , Neuralgia/induzido quimicamente , Neuralgia/genética , Neuralgia/imunologia , Oxaliplatina , Ratos , Ratos Sprague-Dawley , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Objective: Neuropathic pain is common and debilitating with limited effective treatments. Macrophage/microglial activation along ascending somatosensory pathways following peripheral nerve injury facilitates neuropathic pain. However, polarization of macrophages/microglia in neuropathic pain is not well understood. Photobiomodulation treatment has been used to decrease neuropathic pain, has anti-inflammatory effects in spinal injury and wound healing models, and modulates microglial polarization in vitro. Our aim was to characterize macrophage/microglia response after peripheral nerve injury and modulate the response with photobiomodulation. Methods: Adult male Sprague-Dawley rats were randomly assigned to sham (N = 13), spared nerve injury (N = 13), or injury + photobiomodulation treatment groups (N = 7). Mechanical hypersensitivity was assessed with electronic von Frey. Photobiomodulation (980 nm) was applied to affected hind paw (output power 1 W, 20 s, 41cm above skin, power density 43.25 mW/cm 2 , dose 20 J), dorsal root ganglia (output power 4.5W, 19s, in skin contact, power density 43.25 mW/cm 2 , dose 85.5 J), and spinal cord regions (output power 1.5 W, 19s, in skin contact, power density 43.25 mW/cm 2 , dose 28.5 J) every other day from day 7-30 post-operatively. Immunohistochemistry characterized macrophage/microglial activation. Results: Injured groups demonstrated mechanical hypersensitivity 1-30 days post-operatively. Photobiomodulation-treated animals began to recover after two treatments; at day 26, mechanical sensitivity reached baseline. Peripheral nerve injury caused region-specific macrophages/microglia activation along spinothalamic and dorsal-column medial lemniscus pathways. A pro-inflammatory microglial marker was expressed in the spinal cord of injured rats compared to photobiomodulation-treated and sham group. Photobiomodulation-treated dorsal root ganglion macrophages expressed anti-inflammatory markers. Conclusion: Photobiomodulation effectively reduced mechanical hypersensitivity, potentially through modulating macrophage/microglial activation to an anti-inflammatory phenotype.
Assuntos
Modelos Animais de Doenças , Terapia com Luz de Baixa Intensidade/métodos , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Microglia/imunologia , Neuralgia/imunologia , Neuralgia/terapia , Animais , Masculino , Neuralgia/patologia , Tratamentos com Preservação do Órgão , Medição da Dor , Traumatismos dos Nervos Periféricos/imunologia , Traumatismos dos Nervos Periféricos/terapia , Ratos , Ratos Sprague-Dawley , Resultado do TratamentoRESUMO
Oxaliplatin, a chemotherapy drug used to treat colorectal cancer, induces specific sensory neurotoxicity signs that are aggravated by cold and mechanical stimuli. Here we examined the preventive effects of Bee Venom (BV) derived phospholipase A2 (bvPLA2) on oxaliplatin-induced neuropathic pain in mice and its immunological mechanism. The cold and mechanical allodynia signs were evaluated by acetone and von Frey hair test on the hind paw, respectively. The most significant allodynia signs were observed at three days after an injection of oxaliplatin (6 mg/kg, i.p.) and then decreased gradually to a normal level on days 7-9. The oxaliplatin injection also induced infiltration of macrophages and upregulated levels of the pro-inflammatory cytokine interleukin (IL)-1ß in the lumbar dorsal root ganglia (DRG). Daily treatment with bvPLA2 (0.2 mg/kg, i.p.) for five consecutive days prior to the oxaliplatin injection markedly inhibited the development of cold and mechanical allodynia, and suppressed infiltration of macrophages and the increase of IL-1ß level in the DRG. Such preventive effects of bvPLA2 were completely blocked by depleting regulatory T cells (Tregs) with CD25 antibody pre-treatments. These results suggest that bvPLA2 may prevent oxaliplatin-induced neuropathic pain by suppressing immune responses in the DRG by Tregs.
Assuntos
Analgésicos/uso terapêutico , Venenos de Abelha/química , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Fosfolipases A2/uso terapêutico , Analgésicos/farmacologia , Animais , Temperatura Baixa , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/imunologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/imunologia , Interleucina-1beta/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuralgia/induzido quimicamente , Neuralgia/imunologia , Compostos Organoplatínicos , Oxaliplatina , Fosfolipases A2/farmacologia , Linfócitos T Reguladores/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
UNLABELLED: Neuropathic pain, characterized by spontaneous pain, hyperalgesia and allodynia, is a devastating neurological disease that seriously affects patients' quality of life. We have previously shown that tanshinone IIA (TIIA), an important lipophilic component of Danshen, had significant anti-nociceptive effect in somatic and visceral pain, it is surprisingly noted that few pharmacological studies have been carried out to explore the possible analgesic action of TIIA on neuropathic pain and the underlying mechanisms. Therefore, in the present study, by using spinal nerve ligation (SNL) pain model, the antinociceptive and antihyperalgesic effects of TIIA on neuropathic pain were evaluated by intraperitoneal administration in rats. The results indicated that TIIA dose-dependently inhibited SNL-induced mechanical hyperalgesia. As revealed by OX42 levels, TIIA effectively repressed the activation of spinal microglial activation in SNL-induced neuropathic pain. Meanwhile, TIIA also decreased the expressions of inflammatory cytokines TNF-α and IL-1ß in the spinal cord. Furthermore, TIIA inhibited oxidative stress by significantly rescuing the superoxide dismutase (SOD) activity and decreasing the malondialdehyde (MDA). Moreover, TIIA depressed SNL-induced MAPKs activation in spinal cord. CONCLUSION: Taken together, our study provides evidence that TIIA inhibited SNL-induced neuropathic pain through depressing microglial activation and immune response by the inhibition of mitogen-activated protein kinases (MAPKs) pathways. Our findings suggest that TIIA might be a promising agent in the treatment of neuropathic pain.
Assuntos
Abietanos/farmacologia , Analgésicos/farmacologia , Neuralgia/tratamento farmacológico , Neuroglia/efeitos dos fármacos , Abietanos/administração & dosagem , Analgésicos/administração & dosagem , Animais , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Interleucina-1beta/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Neuralgia/imunologia , Neuralgia/fisiopatologia , Neuroglia/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Cumulating evidence has revealed the effectiveness of acupuncture therapy in relieving pain via immunoregulation. However, its underlying mechanism remains unknown. The present study was designed to determine the changes of immunogenic responses at different time-points of electroacupuncture (EA) interventions in neuropathic pain rats. METHODS: The neuropathic pain model was established by ligature of the left sciatic nerve to induce chronic constriction injury (CCI). EA was applied at Zusanli (ST36) and Yanglingquan (GB34) for the EA groups. The thermal pain threshold was detected with an algesia-detector. The subgroups of plasma and splenic lymphocytes were determined via fluorescence-activated cell sorting. Specific inflammatory cytokines were assayed using an ELISA-based bead multiplex assay. The activities of splenic natural killer (NK) cells and cytotoxic T lymphocytes were detected by methyl thiazolyl tetrazolium colorimetric method. For confirming the involvement of NK cell in EA-analgesia, anti-asialo-ganglio-N-tetraosylceramide (anti-asialo-GM1) antibody was given to CCI rats before EA. RESULTS: Following CCI, the thermal pain threshold of the affected hind footpad was significantly decreased, and increased from the 3rd day to the 12th day after EA interventions, presenting a time-dependent tendency from the 5th day on. From day 3 to 5 of EA interventions, the percentages and activity of splenic NK cells, concentrations of splenic interleukin-2 (IL-2) and beta-endorphin (ß-EP) were significantly increased. Meanwhile, the concentrations of plasma IL-2, IL-1ß and gamma-interferon (IFN-γ) were significantly decreased and returned to the normal level on day 12 following EA. Plasma transforming growth factor-ß (TGF-ß) levels were considerably upregulated on day 5 and 12 following EA. The CD4+/CD8+ T cell ratio was markedly downregulated compared with the control and CCI groups on day 5 and returned to the normal level on day 12 following EA. After depleting NK cells by anti-asialo-GM1 antibody, the increased thermal pain threshold following EA intervention was obviously reduced. CONCLUSIONS: Repeated EA interventions have a time-dependent cumulative analgesic effect in neuropathic pain rats, which is closely associated with its regulatory effects on NK cells, splenic IL-2, ß-EP, and plasma IL-2, IL-1ß, IFN-γ and TGF-ß levels.
Assuntos
Analgesia por Acupuntura , Eletroacupuntura , Células Matadoras Naturais/imunologia , Neuralgia/terapia , Animais , Humanos , Interferon gama/sangue , Interleucina-1beta/sangue , Interleucina-2/sangue , Masculino , Neuralgia/sangue , Neuralgia/imunologia , Ratos , Ratos Wistar , beta-Endorfina/sangueRESUMO
The widespread plant volatile beta-caryophyllene (BCP) was recently identified as a natural selective agonist of the peripherally expressed cannabinoid receptor 2 (CB2). It is found in relatively high concentrations in many spices and food plants. A number of studies have shown that CB2 is critically involved in the modulation of inflammatory and neuropathic pain responses. In this study, we have investigated the analgesic effects of BCP in animal models of inflammatory and neuropathic pain. We demonstrate that orally administered BCP reduced inflammatory (late phase) pain responses in the formalin test in a CB2 receptor-dependent manner, while it had no effect on acute (early phase) responses. In a neuropathic pain model the chronic oral administration of BCP attenuated thermal hyperalgesia and mechanical allodynia, and reduced spinal neuroinflammation. Importantly, we found no signs of tolerance to the anti-hyperalgesic effects of BCP after prolonged treatment. Oral BCP was more effective than the subcutaneously injected synthetic CB2 agonist JWH-133. Thus, the natural plant product BCP may be highly effective in the treatment of long lasting, debilitating pain states. Our results have important implications for the role of dietary factors in the development and modulation of chronic pain conditions.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Modelos Animais de Doenças , Neuralgia/tratamento farmacológico , Receptor CB2 de Canabinoide/agonistas , Neuropatia Ciática/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/administração & dosagem , Agonistas de Receptores de Canabinoides/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/imunologia , Hiperalgesia/metabolismo , Masculino , Camundongos , Camundongos Congênicos , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuralgia/imunologia , Neuralgia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/metabolismo , Medição da Dor , Compostos Fitoquímicos/administração & dosagem , Compostos Fitoquímicos/efeitos adversos , Compostos Fitoquímicos/uso terapêutico , Sesquiterpenos Policíclicos , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/imunologia , Nervo Isquiático/metabolismo , Neuropatia Ciática/imunologia , Neuropatia Ciática/metabolismo , Sesquiterpenos/administração & dosagem , Sesquiterpenos/efeitos adversos , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/metabolismoRESUMO
The purpose of this study is to investigate the possible different cellular marker expression associated with spinal cord microglial activation in different pain models. Immunohistochemistry and western blotting analysis of CD45, CD68, and MHC class I antigen as well as CD11b and Iba-1 in the spinal cord were quantitatively compared among widely used three pain animal models, complete Freund's adjuvant (CFA) injection, formalin injection, and chronic constriction injury (CCI) models. The results showed that significant upregulated expressions of CD45 and MHC class I antigen in spinal microglia as well as morphological changes with increased staining with CD11b and Iba-1 were seen in CCI and formalin models and not found in CFA-induced inflammatory pain model. CD68 expression was only detected in CCI model. Our findings suggested that different peripheral tissue injuries produced differential phenotypic changes associated with spinal microglial activation; peripheral nerve injury might induce spinal microglia to acquire these immunomolecular phenotypic changes.
Assuntos
Microglia/patologia , Neuralgia/patologia , Dor/patologia , Traumatismos dos Nervos Periféricos/patologia , Medula Espinal/patologia , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/imunologia , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/imunologia , Modelos Animais de Doenças , Formaldeído , Adjuvante de Freund , Regulação da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/imunologia , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/imunologia , Microglia/imunologia , Neuralgia/induzido quimicamente , Neuralgia/imunologia , Dor/induzido quimicamente , Dor/imunologia , Traumatismos dos Nervos Periféricos/imunologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/imunologiaRESUMO
BACKGROUND: Injury to a nerve is the most common reason of acquired peripheral neuropathy. Therefore, searching for effective substance to recover of nerve after injury is need of present era. The current study investigates the protective potential of Standardized Fruit Extract of Punica granatum L (PFE) [Ellagic acid (41.6%), Punicalagins (10%), Granatin (5.1%)] in Tibial & Sural Nerve Transection (TST) induced neuropathic pain in rats. METHODS: TST was performed by sectioning tibial and sural nerve portions of the sciatic nerve and leaving the common peroneal nerve intact. Acetone drop, pin-prick, hot plate, paint brush & Walking Track tests were performed to assess cold allodynia; mechanical heat, hyperalgesia and dynamic mechanical allodynia & tibial functional index respectively. The levels of TNF-α, TBARS, GSH and Nitrite were measured in the sciatic nerve as an index of inflammation & oxidative stress. RESULTS: TST led to significant development of cold allodynia; mechanical and heat hyperalgesia; dynamic mechanical allodynia; functional deficit in walking along with rise in the levels of TBARS, TNF-α, GSH and Nitrite. Administrations of PFE (100 & 300 mg/kg oral), significantly attenuate TST induced behavioral & biochemical changes. Pretreatments of BADGE (120 mg/kg IP) a PPAR-γ antagonist and nitric oxide precursor L-arginine (100 mg/kg IP) abolished the protective effect of PFE. Whereas, pretreatment of L-NAME (5 mg/kg IP) a NOS inhibitor significantly potentiated PFE's protective effect of PFE. CONCLUSION: PFE shown to have attenuating effect in TST induced neuropathic pain which may be attributed to potential PPAR-gamma agonistic activity, nitric oxide inhibitory, anti-inflammatory and anti oxidative actions.
Assuntos
Anti-Inflamatórios/administração & dosagem , Lythraceae/química , Neuralgia/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Nervo Sural/lesões , Nervo Tibial/lesões , Animais , Arginina/imunologia , Feminino , Frutas/química , Humanos , Masculino , Neuralgia/genética , Neuralgia/imunologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Nervo Sural/efeitos dos fármacos , Nervo Tibial/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Current treatments for neuropathic pain are far from satisfactory. Considering the essential contribution of central immune factors to the pathogenesis of neuropathic pain, targeting inflammatory response is well accepted as an effective strategy for treating neuropathic pain. Triptolide has a long history in traditional Chinese medicine for treating inflammatory diseases and has been proven to inhibit cytokines released from glial cells. OBJECTIVE: In the present study, we tested whether systemic treatment with triptolide could prevent or attenuate nocifensive behaviors associated with neuropathic pain. We further tried to explore the underlying mechanism of the potential anti-allodynia effect of triptolide. STUDY DESIGN: A randomized, double blind, controlled animal trial. METHODS: Triptolide was administered systemically in a rat model of neuropathic pain induced by spinal nerve ligation (SNL) in the single bolus and repeated treatment manners. In the single bolus treatment experiment, triptolide (30 ug/kg, 100 ug/kg, 300 ug/kg) or vehicle was given to SNL and sham-operated rats once on day 1 or on day 10 after surgery (n = 6 each). In the repeated treatment study, prophylactic treatment with triptolide (30 ug/kg, 100 ug/kg, 300 ug/kg) was given to rats during the period of day -3 (3 days prior to SNL) to day 7 (7 days post-SNL) inclusively (n = 6 each). Another set of SNL and sham rats on postoperative day 10 received treatment with triptolide (30 ug/kg, 100 ug/kg, 300 ug/kg) or vehicle during the period of days 11-20 inclusively (n = 6 each), to assess potential reversal of established pain behavior. Mechanical allodynia of the rats was tested with von Frey filaments. Astrocytic and microglial activation in the spinal dorsal horn was evaluated with immunofluorescent histochemistry. Phosphorylation of mitogen-activated protein kinases (MAPKs), and expression of inflammatory cytokines (interleukin-6, interleukin-1beta, monocyte chemotactic protein-1, and tumor necrosis factor-alpha) were examined with Western blot analysis and real-time reverse transcription polymerase chain reaction study. RESULTS: A single bolus treatment with triptolide could neither prevent the induction nor reverse the maintenance of SNL-induced mechanical allodynia. However, repeated administration of triptolide dose-dependently inhibited neuropathic pain behavior in both preventative and interventional paradigms. Triptolide hampered SNL-induced activation of glial cells (astrocytes and microglia) in the spinal dorsal horn without influencing neurons. In addition, SNL-induced phosphorylation of MAPKs could be inhibited by triptolide. Furthermore, up-regulated expression of inflammatory cytokines in neuropathic pain states could be remarkably blocked by triptolide. LIMITATIONS: The direct target site (such as a specific receptor) of triptolide is still to be determined. In addition, triptolide could not completely block the SNL-induced mechanical allodynia. CONCLUSIONS: Our data suggest that triptolide may be a potential novel treatment for neuropathic pain through modulating immune response in the spinal dorsal horn.
Assuntos
Analgésicos/administração & dosagem , Diterpenos/administração & dosagem , Neuralgia/tratamento farmacológico , Fenantrenos/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Western Blotting , Citocinas/biossíntese , Modelos Animais de Doenças , Compostos de Epóxi/administração & dosagem , Imuno-Histoquímica , Masculino , Neuralgia/imunologia , Neuralgia/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/metabolismoRESUMO
BACKGROUND: The development of hyperalgesia and allodynia after chronic constrictive injury (CCI) is associated with significantly increased tumor necrosis factor (TNF)-α and interleukin (IL)-1ß. Theoretically, if the production of TNF-α and/or IL-1ß could be reduced, neuropathic pain syndrome may be alleviated. Recently, a beneficial effect of hyperbaric oxygenation therapy (HBOT) in the treatment of pain disorders has been suggested. Our present study was designed to examine the hypotheses that (1) CCI-induced neuropathic pain may be associated with increased production of TNF-α and IL-1ß, (2) HBOT may alleviate CCI-induced neuropathic pain, and (3) the alleviated neuropathic pain may be associated with reduced production of TNF-α and/or IL-1ß. METHODS: Male rats (weighing 250-300 g) were anesthetized with ketamine and xylazine. The common sciatic nerve was exposed through the biceps femoris. Proximal to the sciatic's trifurcation, 4 ligatures were loosely tied around the nerve. In the sham group, an identical dissection was performed without ligation of the sciatic nerve. Mechanical allodynia and cold allodynia were tested by von Frey filament stimulation and the spread of acetone, respectively. HBO rats (n =18) were exposed to pure oxygen for 1 hour at 2.4 atm once a day. Non-HBO (n =18) and sham rats (n =6) were placed in the HBOT chamber breathing air. TNF-α and IL-1ß in the sciatic nerve were assayed with ELISA. The presence of TNF-α protein in homogenates was verified by Western blot analysis. RESULTS: CCI induced significant cold and mechanical allodynia as measured after CCI on days 4 and 7. The cold allodynia response frequency was significantly lower in HBO rats than in non-HBO rats. The values were 20% ± 1.6% vs 50% ± 4.5% on day 4 and 40% ± 4.6% vs 70% ± 4.5% on day 7 (F =87.42, confidence interval [for the difference between HBO and non-HBO]=29.612 ± 8.781, P < 0.05 for day 4 and day 7). The threshold of mechanical allodynia significantly increased in HBO rats compared with non-HBO rats. The values were 6.20 ± 0.9 vs 4.1 ± 1.0 g on day 4 and 3.8.2 ± 0.5 vs 2.3 ± 0.4 g on day 7 (F =18.8, confidence interval [for the difference between HBO and non-HBO]=1.806 ± 1.171, P < 0.05 for day 4 and day 7). TNF-α content was significantly higher in non-HBO rats than in sham rats on day 4 (17.89 ± 0.83 vs 10.66 ± 1.1 pg/mg protein, P < 0.05) and day 7 (18.97 ± 1.57 vs 9.09 ± 1.5 pg/mg protein, P < 0.05). HBOT significantly reduced TNF-α content to near the level in sham rats, which was 10.94 ± 2.78 and 11.32 ± 2.98 pg/mg protein on day 4 (P < 0.05 versus non-HBO) and 7 (P < 0.05 versus non-HBO), respectively. Western blot analysis confirmed the presence of proteins with molecular weights of 51 kDa in the rat sciatic nerve homogenates. IL-1ß content was also significantly higher in non-HBO rats than in sham rats on day 4 (636 ± 74 vs 256 ± 31 pg/mg protein, P < 0.05) and on day 7 (687 ± 89 vs 288 ± 35 pg/mg protein, P < 0.05). HBOT had no effect on IL-1ß content, which was 671 ± 85 pg/mg protein on day 4 and 672 ± 75 pg/mg protein on day 7 in HBO rats (P =not significant versus non-HBO rats). CONCLUSION: These data show that HBOT alleviates CCI-induced neuropathic pain and inhibits endoneuronal TNF-α production, but not IL-1ß in CCI-induced neuropathic pain. Reduced TNF-α production may, at least in part, contribute to the beneficial effect of HBOT.