P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury
P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury
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DOI：
10.1038/nature01786
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发表时间：
2003-08-14
期刊：
影响因子：
64.8
通讯作者：
Inoue, K
中科院分区：
文献类型：
--
作者：
Tsuda, M;Shigemoto-Mogami, Y;Inoue, K
神经损伤后的疼痛是神经系统病理操作的表现1，2，其中一个标志是由无害刺激引起的触觉异常性疼痛超敏反应。这种疼痛缺乏有效的治疗方法，并且对潜在的机制知之甚少。在此，我们报告了脊髓P2 X（4）受体（P2 X（4）Rs）（3-7）（离子型ATP受体的一种亚型（8））的药理学阻断，逆转了由外周神经损伤引起的触觉异常性疼痛，而不影响幼稚动物的急性疼痛行为。神经损伤后，同侧脊髓P2 X（4）R表达显著增加，在过度活跃的小胶质细胞中诱导P2 X（4）R表达，而在神经元或星形胶质细胞中不诱导P2 X（4）R表达。脊髓内注射P2 X（4）R反义寡核苷酸可减少神经损伤后P2 X（4）R的诱导，并抑制触觉异常性疼痛。相反，脊髓内注射P2 X（4）受体被诱导和刺激的小胶质细胞，在幼稚大鼠中产生触觉异常性疼痛。总之，我们的结果表明，在过度活跃的小胶质细胞中P2 X（4）Rs的激活是神经损伤后触觉异常性疼痛所必需的，并且足以在正常动物中产生触觉异常性疼痛。因此，阻断小胶质细胞中的P2 X（4）Rs可能是神经损伤引起的疼痛的一种新的治疗策略。
Pain after nerve damage is an expression of pathological operation of the nervous system 1,2, one hallmark of which is tactile allodynia-pain hypersensitivity evoked by innocuous stimuli. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. Here we report that pharmacological blockade of spinal P2X(4) receptors (P2X(4)Rs)(3-7), a subtype of ionotropic ATP receptor(8), reversed tactile allodynia caused by peripheral nerve injury without affecting acute pain behaviours in naive animals. After nerve injury, P2X(4)R expression increased strikingly in the ipsilateral spinal cord, and P2X(4)Rs were induced in hyperactive microglia but not in neurons or astrocytes. Intraspinal administration of P2X(4)R antisense oligodeoxynucleotide decreased the induction of P2X(4)Rs and suppressed tactile allodynia after nerve injury. Conversely, intraspinal administration of microglia in which P2X(4)Rs had been induced and stimulated, produced tactile allodynia in naive rats. Taken together, our results demonstrate that activation of P2X(4)Rs in hyperactive microglia is necessary for tactile allodynia after nerve injury and is sufficient to produce tactile allodynia in normal animals. Thus, blocking P2X(4)Rs in microglia might be a new therapeutic strategy for pain induced by nerve injury.