P2Y12 receptor Upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain
P2Y12 receptor Upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain
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DOI：
10.1523/jneurosci.5589-07.2008
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发表时间：
2008-03-12
影响因子：
5.3
通讯作者：
Noguchi, Koichi
中科院分区：
文献类型：
--
作者：
Kobayashi, Kimiko;Yamanaka, Hiroki;Noguchi, Koichi
脊髓中的小胶质细胞可能在神经病理性疼痛的发生和维持中起重要作用。一种代谢型ATP受体P2 Y（12）已被证明在脊髓小胶质细胞中组成型表达，并参与趋化性。p38丝裂原活化蛋白激酶（MAPK）的激活发生在神经损伤后的脊髓小胶质细胞中，可能与细胞因子和其他介质的产生有关，导致神经病理性疼痛。采用大鼠坐骨神经部分结扎（PSNL）模型，发现P2 Y（12）mRNA和蛋白在脊髓中表达增加，并在PSNL后3d达到高峰。双标记研究显示，神经损伤后表达增加的P2 Y（12）mRNA和蛋白的细胞仅为小胶质细胞。鞘内注射P2 Y（12）拮抗剂和反义敲低P2 Y（12）表达均抑制PSNL后脊髓小胶质细胞疼痛行为的发生和p38 MAPK的磷酸化。鞘内注射P2 Y（12）激动剂2-（甲硫基）腺苷5 '-二磷酸三钠盐模拟神经损伤诱导的小胶质细胞中p38的激活和疼痛行为的增强。这些数据提示了神经病理性疼痛的一种新机制，其中P2 Y（12）的增加是神经损伤后小胶质细胞中以下事件的门户。通过释放的ATP或水解产物激活该受体激活p38 MAPK通路，并且可能在神经病理性疼痛的产生中起关键作用。
Microglia in the spinal cord may play an important role in the development and maintenance of neuropathic pain. A metabotropic ATP receptor, P2Y(12), has been shown to be expressed in spinal microglia constitutively and be involved in chemotaxis. Activation of p38 mitogen-activated protein kinase (MAPK) occurs in spinal microglia after nerve injury and may be related to the production of cytokines and other mediators, resulting in neuropathic pain. However, it remains unknown whether any type of P2Y receptor in microglia is involved in the activation of p38 MAPK and the pain behaviors after nerve injury.Using the partial sciatic nerve ligation (PSNL) model in the rat, we found that P2Y(12) mRNA and protein increased in the spinal cord and peaked at 3 d after PSNL. Double labeling studies revealed that cells expressing increased P2Y(12) mRNA and protein after nerve injury were exclusively microglia. Both pharmacological blockades by intrathecal administration of P2Y(12) antagonist and antisense knockdown of P2Y(12) expression suppressed the development of pain behaviors and the phosphorylation of p38 MAPK in spinal microglia after PSNL. The intrathecal infusion of the P2Y(12) agonist 2-(methythio) adenosine 5'-diphosphate trisodium salt into naive rats mimicked the nerve injury-induced activation of p38 in microglia and elevated pain behaviors.These data suggest a new mechanism of neuropathic pain, in which the increased P2Y(12) works as a gateway of the following events in microglia after nerve injury. Activation of this receptor by released ATP or the hydrolyzed products activate p38 MAPK pathway and may play a crucial role in the generation of neuropathic pain.