Objective:To evaluate the effect of down-regulation of Nav1.7 on the activation of astrocytes and microglia in DRG of rats with cancer pain,and explore the transmission of the nociceptive information.Methods:Lentivira...Objective:To evaluate the effect of down-regulation of Nav1.7 on the activation of astrocytes and microglia in DRG of rats with cancer pain,and explore the transmission of the nociceptive information.Methods:Lentiviral vector harboring RNAi sequence targeting the Navl.7 gene was constructed,and Walker 256 breast cancer cell and morphine was injected to build the bone cancer pain model and morphine tolerance model in rats.Lentiviral vector was injected.Rats in each model were divided into 4 groups:model group,PBS group,vehicle group and LV-Nav1.7 group.The expression levels of GFAP and OX42 in dorsal root ganglia(DRG) were measured.Results:After the animal model was built,the level of Navl.7,GFAP and OX42 was improved obviously with the time prolonged,which was statistically significant(P<0.05).The expression level of GFAP and OX42 in the DRG in the LV-Navl.7 group declined obviously compared to the model group,PBS group and vehicle group(P<0.05).Conclusions:Intrathecal injection of Navl.7 shRNA lentiviral vector can reduce the expression of Nav1.7and inhibit the activation of astrocytes and microglia in DRG.The effort is also effective in morphine tolerance bone cancer pain model rats.展开更多
Nitric oxide(NO)/cyclic guanosine 3′,5′-monophosphate(cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the ...Nitric oxide(NO)/cyclic guanosine 3′,5′-monophosphate(cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the NO/cGMP signaling pathway involved in chronic pain, including neuropathic pain, bone cancer pain, inflammatory pain, and morphine tolerance. The main process in the NO/cGMP signaling pathway in cells involves NO activating soluble guanylate cyclase, which leads to subsequent production of cGMP. cGMP then activates cGMP-dependent protein kinase(PKG), resulting in the activation of multiple targets such as the opening of ATP-sensitive K+ channels. The activation of NO/cGMP signaling in the spinal cord evidently induces upregulation of downstream molecules, as well as reactive astrogliosis and microglial polarization which participate in the process of chronic pain. In dorsal root ganglion neurons, natriuretic peptide binds to particulate guanylyl cyclase, generating and further activating the cGMP/PKG pathway, and it also contributes to the development of chronic pain. Upregulation of multiple receptors is involved in activation of the NO/cGMP signaling pathway in various pain models. Notably the NO/cGMP signaling pathway induces expression of downstream effectors, exerting both algesic and analgesic effects in neuropathic pain and inflammatory pain. These findings suggest that activation of NO/cGMP signaling plays a constituent role in the development of chronic pain, and this signaling pathway with dual effects is an interesting and promising target for chronic pain therapy.展开更多
目的:通过骨癌痛(bone cancer pain,BCP)小鼠模型明确右美托咪定是否参与吗啡耐受并探索其机制。方法:使用Lewis肺癌细胞系制备C57BL/6小鼠股骨癌痛动物模型。对BCP小鼠进行鞘内置管,连续7天注射吗啡诱导耐受产生。von Frey纤维丝评估...目的:通过骨癌痛(bone cancer pain,BCP)小鼠模型明确右美托咪定是否参与吗啡耐受并探索其机制。方法:使用Lewis肺癌细胞系制备C57BL/6小鼠股骨癌痛动物模型。对BCP小鼠进行鞘内置管,连续7天注射吗啡诱导耐受产生。von Frey纤维丝评估小鼠左后足50%机械刺激缩足反射阈值(mechanical withdrawal threshold,MWT)、热板法评估热缩足潜伏期阈值(thermal withdrawal threshold,TWL)。给药第7天后取L3~L5节段脊髓,使用免疫组化实验和Western Blotting(WB)方法检测小鼠脊髓Mas相关基因C受体(Mas-related gene C receptor,MrgC)的表达。通过对吗啡耐受的BCP小鼠鞘内注射右美托咪定,探索其可能的机制。结果:自建模后第7天起,BCP小鼠左后足50%MWT显著下降,TWL明显缩短(P<0.05)。建模后第14天起鞘内给予吗啡,给药的第1~4天,BCP小鼠左后足50%MWT明显上升,TWL明显增加(P<0.05),给药的第5天开始50%MWT逐渐下降,TWL明显缩短。但预先鞘内给予右美托咪定后,给药的第1~7天BCP小鼠左后足50%MWT持续增高,TWL持续延长(P<0.05),且免疫组化和WB结果显示MrgC表达明显增加。结论:右美托咪定可缓解BCP小鼠吗啡耐受的形成,这一作用可能与右美托咪定促进BCP小鼠脊髓MrgC表达和活化有关。展开更多
目的:研究鞘内连续注射吗啡联合倍他米松治疗癌性骨痛(cancer-induced bone pain CIBP)的机制。方法:癌性骨痛患者126例,随机分为2组:吗啡组Morphine(M组),鞘内泵入单纯吗啡;吗啡联合倍他米松组Betarmethasone(B组),鞘内泵入吗啡和倍他...目的:研究鞘内连续注射吗啡联合倍他米松治疗癌性骨痛(cancer-induced bone pain CIBP)的机制。方法:癌性骨痛患者126例,随机分为2组:吗啡组Morphine(M组),鞘内泵入单纯吗啡;吗啡联合倍他米松组Betarmethasone(B组),鞘内泵入吗啡和倍他米松(1 mg/周),患者均行椎管内镇痛药物输注港皮下植入术。手术前、手术后第1、3、7天评定疼痛缓解程度、生存质量评分和SF-36量表,手术后第7天测定血浆内啡肽、血浆胃动素和脑脊液中前列腺素E2(PGE2)、P物质(SP)、降钙素基因相关肽(CGRP)。结果:B组爆发痛的次数少于M组(P<0.05);静息卧床时两组疼痛都得到缓解NRS评分<2分,两组比较(P>0.05);B组下床活动后疼痛次数对比吗啡组明显减少(P<0.05);SF-36量表各维度比较B组生活质量有显著改善,日常生活能力得分有显著差异(P<0.05);术后第7天,血浆内啡肽水平,两组比较(P>0.05);血浆胃动素B组高于M组(P<0.05);脑脊液中PGE2、SP、CGRP浓度M组高于B组(P<0.05)。结论:鞘内泵入吗啡联合倍他米松对比鞘内泵入吗啡治疗癌性骨痛,爆发痛的次数减少,改善胃肠动力,提高了患者生存质量。脑脊液中PGE2、SP、CGRP浓度低于鞘内注射吗啡组,可减轻吗啡耐受,增强了镇痛效果。展开更多
基金supported by National Natural Science Foundation of China(NO.81201395)
文摘Objective:To evaluate the effect of down-regulation of Nav1.7 on the activation of astrocytes and microglia in DRG of rats with cancer pain,and explore the transmission of the nociceptive information.Methods:Lentiviral vector harboring RNAi sequence targeting the Navl.7 gene was constructed,and Walker 256 breast cancer cell and morphine was injected to build the bone cancer pain model and morphine tolerance model in rats.Lentiviral vector was injected.Rats in each model were divided into 4 groups:model group,PBS group,vehicle group and LV-Nav1.7 group.The expression levels of GFAP and OX42 in dorsal root ganglia(DRG) were measured.Results:After the animal model was built,the level of Navl.7,GFAP and OX42 was improved obviously with the time prolonged,which was statistically significant(P<0.05).The expression level of GFAP and OX42 in the DRG in the LV-Navl.7 group declined obviously compared to the model group,PBS group and vehicle group(P<0.05).Conclusions:Intrathecal injection of Navl.7 shRNA lentiviral vector can reduce the expression of Nav1.7and inhibit the activation of astrocytes and microglia in DRG.The effort is also effective in morphine tolerance bone cancer pain model rats.
基金supported by the National Natural Science Foundation of China,Nos. 82071556 (to WM), 81873793 (to WM), 82001198 (to YQZ), 82101310 (to DQL)the National Key Research and Development Program of China,No. 2020YFC2005300 (to WM)。
文摘Nitric oxide(NO)/cyclic guanosine 3′,5′-monophosphate(cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the NO/cGMP signaling pathway involved in chronic pain, including neuropathic pain, bone cancer pain, inflammatory pain, and morphine tolerance. The main process in the NO/cGMP signaling pathway in cells involves NO activating soluble guanylate cyclase, which leads to subsequent production of cGMP. cGMP then activates cGMP-dependent protein kinase(PKG), resulting in the activation of multiple targets such as the opening of ATP-sensitive K+ channels. The activation of NO/cGMP signaling in the spinal cord evidently induces upregulation of downstream molecules, as well as reactive astrogliosis and microglial polarization which participate in the process of chronic pain. In dorsal root ganglion neurons, natriuretic peptide binds to particulate guanylyl cyclase, generating and further activating the cGMP/PKG pathway, and it also contributes to the development of chronic pain. Upregulation of multiple receptors is involved in activation of the NO/cGMP signaling pathway in various pain models. Notably the NO/cGMP signaling pathway induces expression of downstream effectors, exerting both algesic and analgesic effects in neuropathic pain and inflammatory pain. These findings suggest that activation of NO/cGMP signaling plays a constituent role in the development of chronic pain, and this signaling pathway with dual effects is an interesting and promising target for chronic pain therapy.
文摘目的:研究鞘内连续注射吗啡联合倍他米松治疗癌性骨痛(cancer-induced bone pain CIBP)的机制。方法:癌性骨痛患者126例,随机分为2组:吗啡组Morphine(M组),鞘内泵入单纯吗啡;吗啡联合倍他米松组Betarmethasone(B组),鞘内泵入吗啡和倍他米松(1 mg/周),患者均行椎管内镇痛药物输注港皮下植入术。手术前、手术后第1、3、7天评定疼痛缓解程度、生存质量评分和SF-36量表,手术后第7天测定血浆内啡肽、血浆胃动素和脑脊液中前列腺素E2(PGE2)、P物质(SP)、降钙素基因相关肽(CGRP)。结果:B组爆发痛的次数少于M组(P<0.05);静息卧床时两组疼痛都得到缓解NRS评分<2分,两组比较(P>0.05);B组下床活动后疼痛次数对比吗啡组明显减少(P<0.05);SF-36量表各维度比较B组生活质量有显著改善,日常生活能力得分有显著差异(P<0.05);术后第7天,血浆内啡肽水平,两组比较(P>0.05);血浆胃动素B组高于M组(P<0.05);脑脊液中PGE2、SP、CGRP浓度M组高于B组(P<0.05)。结论:鞘内泵入吗啡联合倍他米松对比鞘内泵入吗啡治疗癌性骨痛,爆发痛的次数减少,改善胃肠动力,提高了患者生存质量。脑脊液中PGE2、SP、CGRP浓度低于鞘内注射吗啡组,可减轻吗啡耐受,增强了镇痛效果。
