Interleukin-1beta released by microglia initiates the enhanced glutamatergic activity in the spinal dorsal horn during paclitaxel-associated acute pain syndrome.
Interleukin-1beta released by microglia initiates the enhanced glutamatergic activity in the spinal dorsal horn during paclitaxel-associated acute pain syndrome.
复制标题
在紫杉醇相关的急性疼痛综合征期间，小胶质细胞释放的白介素-1β启动脊髓背角谷氨酸能活性的增强。
作者：
Xisheng Yan;Fen Li;Dylan W Maixner;Ruchi Yadav;Mei Gao;Mourad Wagdy Ali;Shelley B Hooks;Han-Rong Weng
接受紫杉醇癌症治疗的患者通常会出现急性疼痛综合征(紫杉醇相关急性疼痛综合征，P-APS)，这种综合征在紫杉醇治疗后立即发生。P-APS的潜在机制在很大程度上仍不清楚。我们最近报道了接受紫杉醇治疗的啮齿动物出现急性疼痛，通过紫杉醇进入脊髓激活脊髓小胶质细胞Toll样受体4(TLR4)是P-APS发生的关键事件。我们目前的研究剖析了P-APS的细胞和分子机制。我们证明了在接受静脉注射的动物中，紫杉醇的洗浴灌流浓度与脑脊液中发现的浓度相似。紫杉醇(2 mg/kg)可使小胶质细胞钙离子活性即刻升高，星形胶质细胞钙离子活性升高6 m in。紫杉醇对小胶质细胞TLR4的激活可使小胶质细胞迅速释放IL-1β(IL-1β)，但不能释放肿瘤坏死因子α、IL-6或干扰素-γ。小胶质细胞释放IL-1β依赖于Capthepsin B，IL-1β作用于星形胶质细胞，导致钙活性升高，抑制谷氨酸摄取。IL-1β还作用于神经元，增加脊髓背角突触前谷氨酸释放和突触后AMPA受体活性。敲除IL-1受体可阻止紫杉醇诱导的小鼠急性疼痛的发展。我们的研究表明，在P-AP的发生过程中，IL-1β是小胶质细胞在TLR4激活后改变星形胶质细胞和神经元功能的关键分子，靶向调节小胶质细胞产生和功能IL-1β的信号通路是开发治疗P-AP的止痛药的潜在途径。
Patients receiving paclitaxel for cancer treatment often develop an acute pain syndrome (paclitaxel‐associated acute pain syndrome, P‐APS), which occurs immediately after paclitaxel treatment. Mechanisms underlying P‐APS remain largely unknown. We recently reported that rodents receiving paclitaxel develop acute pain and activation of spinal microglial toll like receptor 4 (TLR4) by paclitaxel penetrating into the spinal cord is a critical event in the genesis of P‐APS. Our current study dissected cellular and molecular mechanisms underlying the P‐APS. We demonstrated that bath‐perfusion of paclitaxel, at a concentration similar to that found in the cerebral spinal fluid in animals receiving i.v. paclitaxel (2 mg/kg), resulted in increased calcium activity in microglia instantly, and in astrocytes with 6 min delay. TLR4 activation in microglia by paclitaxel caused microglia to rapidly release interleukin‐1β (IL‐1β) but not tumor necrosis factor α, IL‐6, or interferon‐γ. IL‐1β release from microglia depended on capthepsin B. IL‐1β acted on astrocytes, leading to elevated calcium activity and suppressed glutamate uptake. IL‐1β also acted on neurons to increase presynaptic glutamate release and postsynaptic AMPA receptor activity in the spinal dorsal horn. Knockout of IL‐1 receptors prevented the development of acute pain induced by paclitaxel in mice. Our study indicates that IL‐1β is a crucial molecule used by microglia to alter functions in astrocytes and neurons upon activation of TLR4 in the genesis of P‐APS, and targeting the signaling pathways regulating the production and function of IL‐1β from microglia is a potential avenue for the development of analgesics for the treatment of P‐APS.