Chemokine signaling involving chemokine (C-C motif) ligand 2 plays a role in descending pain facilitation.
Chemokine signaling involving chemokine (C-C motif) ligand 2 plays a role in descending pain facilitation.
复制标题
DOI：
10.1007/s12264-012-1218-6
复制
发表时间：
2012-04
影响因子：
5.6
通讯作者：
Ren, Ke
中科院分区：
文献类型：
--
作者：
Guo, Wei;Wang, Hu;Zou, Shiping;Dubner, Ronald;Ren, Ke
关键词：
尽管越来越多的证据表明免疫细胞及其相关化学物质在疼痛机制中的作用，但很少有研究讨论趋化因子在持续性疼痛下行促进中的潜在作用。本研究旨在验证大鼠延髓头端腹内侧区(RVM)的趋化因子(C-C基序)配体2(CCL2)(俗称单核细胞趋化蛋白-1)信号转导机制参与大鼠下行痛觉易化的假说。在戊巴比妥钠麻醉下建立L5脊神经结扎术(SNL)。用Western印迹和免疫组织化学方法检测CCL2和CCL2受体(CCR2)的表达水平，并分别与神经元标记物Neun和胶质标记物胶质纤维酸性蛋白(GFAP)和CD11b(小胶质细胞)进行比较。SNL可诱导RVM中CCL2的表达增加，伤后4周恢复至对照组水平。诱导的CCL2与NeuN共定位，但不与GFAP和CD11b共定位。SNL还上调了RVM中CCR2的表达，这种上调持续了至少4周。CCR2与CD11b共定位，但不与GFAP共定位。少数RVM神经元也显示CCR2染色。在SNL后第1天，用抗CCL_2抗体(0.2~20 ng)中和CCL_2或向RVM内注射CCR2b趋化因子受体拮抗剂RS-102895(0.1~10pmol)，可显著减轻已建立的热和机械超敏反应。此外，右室注射重组大鼠CCl_2(0.03-3pmoL)可引起剂量依赖性的痛觉过敏，这种作用可被RS-102895(10pmoL)预处理所阻断。IL-1β(IL-1β)是神经元性CCL2的有效诱导剂，在RVM反应性星形胶质细胞中也选择性上调。右室注射IL-1β(120fmoL)引起的行为痛敏，可被RS-102895(10pmo1)阻断。然而，IL-1受体拮抗剂(3pmoL)不能阻止CCL2(3pmoL)引起的痛觉过敏。这些结果表明，CCl_2的作用位于IL-1β信号的下游。IL-1β和CCL2-CCR2信号通路在神经元-神经胶质细胞-细胞因子相互作用和神经病理性疼痛下行易化中发挥作用。
Despite accumulating evidence on a role of immune cells and their associated chemicals in mechanisms of pain, few studies have addressed the potential role of chemokines in the descending facilitation of persistent pain. The present study was undertaken to test the hypothesis that the chemokine (C-C motif) ligand 2 (CCL2) (commonly known as monocyte chemoattractant protein-1) signaling in the rostral ventromedial medulla (RVM), a pivotal structure in brainstem pain modulatory circuitry, is involved in descending pain facilitation in rats. An L5 spinal nerve ligation (SNL) was produced in rats under pentobarbital anesthesia. Western blot and immunohistochemistry were used to detect the expression levels of CCL2 and CCL2 receptor (CCR2), and examine their distributions compared with the neuronal marker NeuN as well as glial markers glial fibrillary acidic protein (GFAP, astroglial) and CD11b (microglial), respectively. SNL induced an increase in CCL2 expression in the RVM, and this returned to the control level at 4 weeks after injury. The induced CCL2 colocalized with NeuN, but not with GFAP and CD11b. CCR2 was also upregulated by SNL in the RVM, and this increase lasted for at least 4 weeks. CCR2 was colocalized with CD11b but not GFAP. Few RVM neurons also exhibited CCR2 staining. Neutralizing CCL2 with an anti-CCL2 antibody (0.2–20 ng) or injecting RS-102895 (0.1–10 pmol), a CCR2b chemokine receptor antagonist, into the RVM on day 1 after SNL, significantly attenuated the established thermal and mechanical hypersensitivity. In addition, injection of recombinant rat CCL2 (0.03–3 pmol) into the RVM induced dose-dependent hyperalgesia, which was prevented by pretreatment with RS-102895 (10 pmol). Interleukin-1β (IL-1β), a potent inducer of neuronal CCL2, was also selectively upregulated in RVM reactive astrocytes. Injection of IL-1β (120 fmol) into the RVM induced behavioral hyperalgesia, which was blocked by RS-102895 (10 pmol). However, an IL-1 receptor antagonist (3 pmol) did not prevent CCL2 (3 pmol)-induced hyperalgesia. These results suggest that the effect of CCL2 is downstream to IL-1β signaling. The IL-1β and CCL2-CCR2 signaling cascades play a role in neuron-glia-cytokine interactions and the descending facilitation of neuropathic pain.
登录
查看更多内容
DOI：
10.1523/jneurosci.1564-11.2011
发表时间：
2011-09-07
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Gu M;Miyoshi K;Dubner R;Guo W;Zou S;Ren K;Noguchi K;Wei F
通讯作者：
Wei F
影响因子：
6.2
作者：
Gao, Yong-Jing;Zhang, Ling;Ji, Ru-Rong
通讯作者：
Ji, Ru-Rong
影响因子：
4.7
作者：
Banisadr, G;Quéraud-Lesaux, F;Parsadaniantz, SM
通讯作者：
Parsadaniantz, SM
影响因子：
2.5
作者：
Baamonde, Ana;Hidalgo, Agustin;Menendez, Luis
通讯作者：
Menendez, Luis
影响因子：
3.3
作者：
Menetski, J.;Mistry, S.;Abbadie, C.
通讯作者：
Abbadie, C.