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ObjectiveTo observe the behavioral and pain threshold alterations， as well as the changes in indexes related to depression and pain in the serum and central system in mice stressed by maternal separation and chronic neuropathic pain， and explore the underlying mechanism of Wenyang prescription （WY）， Jieyu prescription （JY）， and Wenyang Jieyu prescription （WYJY） in improving depression and pain sensitivity. MethodThe birth date of mice was recorded as PD0. After birth， the mice were divided into a blank group and an experimental group. The neonatal mice in the experimental group underwent maternal separation in PD5-14 at 8 h·d-1. After ablactation， the mice were divided into a maternal separation group， a WY group （Erxian decoction， 5.84 g·kg-1）， a JY group （Xiaoyaosan， 12.00 g·kg-1）， a WYJY group （16.68 g·kg-1）， and a fluoxetine group （2.60 mg·kg-1）， with 15 mice in each group. Meanwhile， 15 male mice of the same age without maternal separation were assigned to the normal control group. Mice in the blank group and the maternal separation group were fed on a regular chow diet in PD21-PD90， while the remaining groups were fed on the corresponding drugs. In PD91， sciatic nerve ligation was performed to induce a model of maternal separation and chronic neuropathic pain. The open field test was used to observe the depression-like behaviors of mice in each group， and the mechanical and temperature pain thresholds were measured to detect the pain sensitivity of mice in each group. The serum levels of corticosterone （CORT）， substance P， and β-endorphin （β-EP） were determined by enzyme-linked immunosorbent assay （ELISA）， and the expression of the glucocorticoid receptor （GR） in the amygdala and β-EP protein in the hypothalamus was detected by immunohistochemistry. The mRNA expression levels of amygdala GR gene （Nr3c1）， FK506 binding protein 5 gene （FKBP5）， metabolic glutamate receptor 5 gene （GRM5）， and brain-derived neurotrophic factor （BDNF） were detected by real-time fluorescence quantitative polymerase chain reaction（Real-time PCR）. ResultCompared with the blank group， the maternal separation group showed reduced stay time and total distance traveled in the 5-min open field test （P<0.01）， reduced mechanical pain threshold （P<0.01）， increased serum CORT and β-EP （P<0.01）， declining FKBP5 mRNA expression （P<0.01）， and increased hypothalamic β-EP expression （P<0.05）. Compared with the maternal separation group， the groups with drug intervention showed prolonged stay time （P<0.05， P<0.01） and up-regulated pain thresholds to different degrees. The total distance traveled in the 5-min open field test increased in the WY group， the WYJY group， and the fluoxetine group （P<0.05， P<0.01）. The JY group showed decreased serum CORT （P<0.01）， reduced β-EP ， and increased BDNF mRNA （P<0.01）. Nr3c1 and GRM5 mRNA decreased in the WY group （P<0.05， P<0.01）. The WYJY group showed decreased serum CORT （P<0.05）and decreased Nr3c1， GRM5， and BDNF mRNA （P<0.05， P<0.01）. The levels of β-EP expression were elevated to different degrees in the groups with drug intervention， but the differences were not significant. The levels of GR expression in the WY group， the JY group， and the WYJY group increased （P<0.05）. ConclusionWYJY can inhibit central pain sensitization and regulate hypothalamic-pituitary-adrenal gland （HPA） axis function by enhancing the expression of GR in the amygdala and inhibiting neuroplasticity and excitability in the amygdala to relieve depression-like behaviors and improve somatic hyperalgesia.
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Mesocorticolimbic dopaminergic (DA) neurons have been implicated in regulating nociception in chronic pain, yet the mechanisms are barely understood. Here, we found that chronic constructive injury (CCI) in mice increased the firing activity and decreased the KCNQ channel-mediated M-currents in ventral tegmental area (VTA) DA neurons projecting to the nucleus accumbens (NAc). Chemogenetic inhibition of the VTA-to-NAc DA neurons alleviated CCI-induced thermal nociception. Opposite changes in the firing activity and M-currents were recorded in VTA DA neurons projecting to the medial prefrontal cortex (mPFC) but did not affect nociception. In addition, intra-VTA injection of retigabine, a KCNQ opener, while reversing the changes of the VTA-to-NAc DA neurons, alleviated CCI-induced nociception, and this was abolished by injecting exogenous BDNF into the NAc. Taken together, these findings highlight a vital role of KCNQ channel-mediated modulation of mesolimbic DA activity in regulating thermal nociception in the chronic pain state.
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As the primary innate immune cells in the central nervous system, microglia can be activated by external noxious stimulus and in turn interact with astroglia and neurons to induce neuroinflammation and facilitate the transmission of pain signals. This response can help the central nervous system adapt to the changes of the internal environment induced by noxious stimulus, leading to the long-term sensitivity of peripheral and central pain nerve conduction pathways and chronic neuropathic pain. Numerous researches found that activation of microglia participated in the occurrence and maintenance of chronic neuropathic pain, and inhibition of microglial activation in the spinal cord or the brain had analgesic effect in animal experiments. Due to the fact that molecular and cellular mechanisms between the activation of microglia and pain remittence are unclear, there are many difficulties in designing of new drugs selectively targeting to the activation of microglia for treatment of chronic neuropathic pain. We review here the research articles on microglia and chronic neuropathic pain, sorting out the relationship between microglia and chronic neuropathic pain, and provide new ideas for the development of new drugs targeting to microglia for the treatment of chronic neuropathic pain.
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OBJECTIVE: To observe the effect of electroacupuncture (EA) on expression of high mobility group protein 1 (HMGB 1) and related downstream effectors of proinflammatory cytokines in the hippocampus in chronic neuropathic pain rats, so as to investigate its mechanism underlying neuropathic pain relief. METHODS: Male SD rats were randomized into sham, model, and EA groups, with 12 rats in each group. The neuropathic pain model was established by ligature of the left sciatic nerve to induce chronic constriction injury (CCI). EA was applied to bilateral "Zusanli"(ST 36) and "Yanglingquan"(GB 34) for 30 min, once daily for 7 days. The mechanical withdrawal threshold (WMT) was detected using an electronic von Frey anesthesiometer. The expression level of HMGB 1 in the hippocampus was determined using quantitative RT-PCR and Western blot, separately, and the contents of hippocampal TNF-α and IL-1 β were detected by ELISA. RESULTS: Compared with the sham group, the MWT values were markedly decreased on day 7, 10 and 14 after modeling in the model group (P<0.001). On day 10 and 14 after modeling, the MWT values were significantly up-regulated in the EA group relevant to those of the model group (P<0.05, P<0.01). The expression levels of HMGB1 mRNA and protein, and the contents of hippocampal TNF-α and IL-1 β were markedly increased in the model group relevant to the sham group (P<0.001), and significantly down-regulated in the EA group relevant to the model group (P<0.001, P<0.01, P<0.05). CONCLUSION: EA stimulation of ST 36-GB 34 can relieve pain in chronic neuropathic pain rats, which may be related to its actions in down-regulating the levels of HMGB 1 and its downstream proinflammatory cytokines TNF-α and IL-1 β in the hippocampus.
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OBJECTIVE: To observe the effect of electroacupuncture (EA) on the expression of high mobility group box 1 (HMGB 1) and its receptor CD 24 proteins and β-endorphin (β-EP) content in "Zusanli" (ST 36) region in rats with chronic constriction injury (CCI), so as to explore its mechanisms underlying pain relief. METHODS: Thirty male Wistar rats were rando-mized into control, CCI model and EA groups (n＝ 10 rats in each). The neuropathic pain model was established by ligature of the left sciatic nerve to induce CCI in the model and EA groups, and sham operation was performed in rats of the control group. Paw with drawal latency (PWL, thermal pain threshold) of the bilateral hind-limbs was detected by using an algesia-detector. Eight days after CCI operation, EA was applied to bilateral "Zusanli" (ST 36) and "Yanglingquan" (GB 34) for 30 min, once daily for 5 days. The acetylated-HMGB 1 expression was determined by immunoprecipitation, and the expression of HMGB 1 and toll like receptor 4 (TLR 4) proteins and CD 24 mRNA were detected using Western blot and fluorescent quantitative real time-PCR, respectively, and the content of β-EP in the acupoint region was assayed by enzyme linked immunosorbent assay (ELISA). Anti-CD 24 neutralizing antibody (200 µL, 100 µg/mL) was injected into ST 36 region once daily for 3 days for verifying the involvement of HMGB 1/CD 24 signaling in EA analgesia. RESULTS: Compared with the control group, the bilateral PWL difference values in the other two groups were significantly increased (P0.05). After local injection of anti-CD 24 antibody, EA-induced increases of β-EP content and reduction of thermal pain threshold were significantly suppressed (P<0.05). CONCLUSION: EA of ST 36 and GB 34 can alleviate neuropathic pain in CCI rats, which is associated with its effects in up-regulating β-EP content, and HMGB 1 protein and CD 24 mRNA expression levels in ST 36 region. The activated HMGB 1/CD 24/β-EP signaling contributes to EA-ST 36 induced analgesia.
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Objective To analyze the effect of intrathecal injection of dexmedetomidine on the behavioral activity, pain degree and expression of protein kinase C in spinal dorsal horn of rat models of chronic neuropathic pain, and to investigate the analgesic mechanism of dexmedetomidine.Methods 75 healthy male rats were randomly divided into observation group, model group and control group, 25 rats in each group.Chronic sciatic nerve injury model was established in the observation group and model group.After modeling, intrathecal dexmedetomidine intervention was used in the observation group.The model group was treated with saline injection and there was no intervention in the control group.Before the modeling (BM)and at 3(D3), 5(D5), 7(D7), and 14 (D14)days after medicine administration, the behavioral capacity was evaluated by cumulative evaluation method and movement function evaluation, and the assessment of pain degree (mechanical withdrawal method and thermal withdrawal latency pain threshold detection method), PKC staining score (immunohistochemical SABC method), PKC mRNA assay (RT-PCR method) and PKC protein expression (Western blot) were conducted and the data were statistically analyzed.Results ① Before modeling, the behavior, the cumulative scores of motor function, MWT, and TWL showed no significant differences between the different groups (P>0.05).After modeling, the model group and observation group showed that the cumulative scores and motor function scores were increased significantly, MWT and TWL decreased significantly, and the changes in the observation group were significantly lower than those in the model group (P<0.05).After modeling, the cumulative scores, motor function scores, MWT, and TWL were significantly different between the groups (P<0.05).② The expression of PKC was negative in the control group and positive in the model group.In the observation group, after the initial establishment of model, the PKC was strongly positive, and along with the prolonged treatment, the PKC expression intensity was decreased, and only weakly positively expressed at 14 d.③ After modeling, the observation group and model group showed that the PKC mRNA and PKC protein expression levels were significantly higher than that of the control group (P<0.05).With the continuous drug administration, the PKC mRNA and PKC in the observation group were decreasing, and reached a level close to that of the control group at 14 d of drug administration.From the third day after modeling, at the same time points, the amount of PKC expression in the observation group was significantly lower than that in the model group (P<0.05).Conclusions Intrathecal injection of dexmedetomidine can improve the behavior of rat models with chronic neuropathic pain, and reduce the degree of pain.It may be related to the inhibition of protein kinase C expression in the spinal dorsal horn.
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Objective To observe the distribution and possible mechanism of P2X7R in periaq-ueductal gray matter (PAG)in a rat model with chronic neuropathic pain in vivo.Methods The in-trathecal catheterization and sciatic nerve injury (SNI)were performed.All animals were randomly assigned into 3 groups with 26 rats in each,which was group Sham,control group (group C)and brilliant blue G (BBG)group (group BBG),respectively.Normal saline or BBG 10 μl were intrathe-cally injected after SNI and repeated for seven days.Paw-withdrawal mechanical thresholds (PWT) were measured on day 0,day 7,day 14,and day 21 after SNI.The rats were sacrificed and PAG tis-sues were collected on day 14 and day 21,separately.The distributions of P2X7R were observed by immunofluorescence.The protein contents of P2X7R and GFAP were assessed by Western blot assays.Results The P2X7R was expressed in PAG in rats.The PWTs of the control group showed a significant decrease during the 21-day period compared with the sham group.The P2X7R signals were predominantly expressed in astrocytes in PAG after SNI.Both P2X7R and GFAP expression remark-ably increased.Administration of BBG increased the PWTs,and inhibited the P2X7R and GFAP ex-pressions compared with those atthe same point of time of the control group.Conclusion These results indicated that P2X7R in PAG might participate in nociception modulation in the midbrain in chronic neuropathic pain.
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ABSTRACT BACKGROUND AND OBJECTIVES: Central pain, classified as neuropathic, is defined as a painful syndrome caused by injury to central nervous system structures. This is one of the most complexes, intriguing and difficult to treat syndromes. This study aimed at promoting a narrative review including the concept of central pain, its intercurrent symptoms which are important for the diagnosis, and different available treatments, indications, results and complications. CONTENTS: Relevant articles available in Medline, Scielo, Cochrane Library and Pubmed databases in the last 10 years were selected by means of keywords: chronic neuropathic pain, central neuropathic pain, central pain. CONCLUSION: Central painful syndrome is diagnosed by means of neurological clinical evaluation. It is often refractory to clinical and neuromodulatory treatment, its management should be multimodal and allow for rehabilitation.
RESUMO JUSTIFICATIVA E OBJETIVOS: A dor central, classificada como neuropática, é definida como uma síndrome dolorosa que decorre da lesão de estruturas no sistema nervoso central. Trata-se de uma das síndromes dolorosas mais complexas, intrigantes e de difícil tratamento. O objetivo deste estudo foi promover uma revisão narrativa que inclui desde o conceito de dor central, seus sintomas intercorrentes importantes no diagnóstico; e diversos tratamentos disponíveis, indicações, resultados e complicações. CONTEÚDO: Foi realizada uma seleção de artigos relevantes disponíveis nas plataformas Medline, Scielo, Biblioteca Cochrane e Pubmed nos últimos 10 anos, por meio dos descritores: dor crônica neuropática, dor neuropática central, dor central. CONCLUSÃO: A síndrome dolorosa central tem seu diagnóstico realizado por meio do exame clínico neurológico. É frequentemente refratária ao tratamento clínico e neuromodulatório e, portanto, deve ser multimodal e permitir a reabilitação.
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JUSTIFICATIVA E OBJETIVOS: O uso da estimulação elétrica de nervos periféricos para o tratamento da dor crônica constitui um armamentário neurocirúrgico utilizado há bastante tempo, sendo uma modalidade indicada no tratamento das síndromes dolorosas de caráter neuropático, juntamente com outras formas de neuroestimulação: estimulação elétrica da coluna dorsal e a estimulação cerebral profunda. O objetivo deste estudo foi analisar a relevância da estimulação nervosa periférica no tratamento das síndromes dolorosas crônicas. CONTEÚDO: A principal indicação é a dor neuropática crônica, intensa, refratária ao tratamento conservador. Apresenta, contudo, necessidade de a área acometida ter uma distribuição anatômica definida e relacionada ao nervo periférico no qual se deseja realizar a estimulação. Deve-se perceber também sinais de comprometimentoobjetivo do nervo. É necessária a realização de teste de neuroestimulação entre 7 e 10 dias previamente ao implante definitivo e deve-se obter melhora de pelo menos 50% da dor em escalas de avaliação específicas. Existem duas formas de implante de eletrodo em nervos periféricos: abordagem cirúrgica direta e técnica percutânea. Após o teste ser completado, é realizado o implante do sistema de gerador permanente. CONCLUSÃO: O uso da estimulação de nervos periféricos no tratamento das síndromes dolorosas crônicas tem mostrado resultados promissores. O desenvolvimento de novos materiais é extremamente necessário para a evolução da técnica e o tratamento dessas síndromes dolorosas crônicas. Nesse sentido, novas próteses estão sendo desenvolvidas e uma das características de implante mais viável para uso no sistema nervoso periférico seria uma prótese de baixo perfil, com bateria já implantada com os eletrodos e recarregável.
BACKGROUND AND OBJECTIVES: Peripheral nerve stimulation to treat chronic pain is a neurosurgical armamentarium used for a long time, being indicated to treat neuropathic painful syndromes together with other types of nerve stimulation: dorsal column electric stimulation and deep cerebral stimulation. This study aimed at analyzing the relevance of peripheral nerve stimulation to treat chronic painful syndromes. CONTENTS: Primary indication is severe chronic neuropathic pain refractory to conservative treatment. However, the affected area needs to have a defined anatomic distribution and related to the peripheral nerve to be stimulated. One should also notice signs of objective involvement of the nerve. A nerve stimulation test shall be performed from 7 to 10 days prior to the final implant and pain must improve at least 50% according to specific evaluation scales. There are two methods to implant electrodes in peripheral nerves: direct surgical approach and percutaneous technique. After the test, the implant with permanent generator is performed. CONCLUSION: Peripheral nerve stimulation to treat chronic painful syndromes has shown promising results. The development of new materials is extremely necessary for the technical evolution and treatment of chronic painful syndromes. In this sense, new prostheses are being developed and one feature of a more feasible implant to be used in the peripheral nervous system would be low profile prosthesis with already implanted and rechargeable battery.
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Postherpetic neuralgia (PHN) is a debilitating complication of herpes zoster, especially in elderly and comorbid patients. Unfortunately, the currently available treatments have shown limited efficacy and some adverse events that are poorly tolerated in elderly patients. Scrambler Therapy, proposed as an alternative treatment for chronic neuropathic pain recently, is a noninvasive approach to relieve pain by changing pain perception at the brain level. Here, we report our clinical experiences on the effect of Scrambler Therapy for three patients with PHN refractory to conventional treatment.
Subject(s)
Aged , Humans , Brain , Herpes Zoster , Neuralgia , Neuralgia, Postherpetic , Pain PerceptionABSTRACT
@# Pulsed radiofrequency (PRF) which can form high voltage around the tissues by emitting pulsed electric current may affect activity of synapses and cytokine. It has many advantages, such as smaller trauma, easier manipulation, safer, better effect, and so on.
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Objective To explore the influence of chronic neuropathic pain on cellular immune function of mice models.Methods The mice models were established by ligating tibeal nerve and common peroneal nerve on one side,and the influence of chronic neuropathic pain on cellular immune function and tumor necrosis factor-?(TNF-?) and interleukin-6(IL-6) was observed with lymphocyte cell increase experiment(MTT method) and enzyme linked immunosorbent assay(ELISA).Results The increased reactivity of T lymphocyte of the model group was significantly higher than that of the sham group and the control group.At the same time,content of TNF-? and IL-6 in blood of the model group also increased.Conclusion Cellular immune function of mice is increased in the state of chronic neuropathic pain.