P2X receptors‐mediated cytosolic phospholipase A2 activation in primary afferent sensory neurons contributes to neuropathic pain
P2X receptors‐mediated cytosolic phospholipase A2 activation in primary afferent sensory neurons contributes to neuropathic pain
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DOI：
10.1111/j.1471-4159.2007.04861.x
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发表时间：
2007-11
影响因子：
4.7
通讯作者：
M. Tsuda;S. Hasegawa;Kazuhide Inoue
中科院分区：
文献类型：
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作者：
M. Tsuda;S. Hasegawa;Kazuhide Inoue
P2 X3和P2 X2/3受体（P2 X3 R/P2 X2/3R），离子型ATP受体亚型，在初级感觉神经元中的激活参与神经性疼痛，一种在外周神经损伤后发生的使人衰弱的慢性疼痛。然而，其潜在机制仍不清楚。我们研究了胞浆磷脂酶A2（cPLA 2）作为介导P2 X3 R/P2 X2/3R依赖性神经性疼痛的下游分子的作用。我们发现，将ATP应用于培养的背根神经节（DRG）神经元增加Ser 505-磷酸化cPLA 2的水平，并导致Ser 505-磷酸化cPLA 2易位到质膜。ATP诱导的cPLA 2激活被P2 X3 R/P2 X2/3R的选择性拮抗剂和cPLA 2的选择性抑制剂抑制。在体内DRG中，cPLA 2激活的神经元的数量在外周神经损伤后显著增加，但在完全弗氏佐剂产生的外周炎症后没有增加。P2 X3 R/P2 X2/3R的药理学阻断逆转了DRG神经元中神经损伤诱导的cPLA 2活化。此外，在DRG附近施用cPLA 2抑制剂抑制神经损伤诱导的触觉异常性疼痛，这是神经性疼痛的标志。我们的研究结果表明，初级感觉神经元中P2 X3 R/P2 X2/3R依赖的cPLA 2活性是神经病理性疼痛的关键事件，cPLA 2可能是治疗神经病理性疼痛的潜在靶点。
Activation of P2X3 and P2X2/3 receptors (P2X3R/P2X2/3R), ionotropic ATP receptor subtypes, in primary sensory neurons is involved in neuropathic pain, a debilitating chronic pain that occurs after peripheral nerve injury. However, the underlying mechanisms remain unknown. We investigated the role of cytosolic phospholipase A2 (cPLA2) as a downstream molecule that mediates the P2X3R/P2X2/3R‐dependent neuropathic pain. We found that applying ATP to cultured dorsal root ganglion (DRG) neurons increased the level of Ser505‐phosphorylated cPLA2 and caused translocation of Ser505‐phosphorylated cPLA2 to the plasma membrane. The ATP‐induced cPLA2 activation was inhibited by a selective antagonist of P2X3R/P2X2/3R and by a selective inhibitor of cPLA2. In the DRG in vivo, the number of cPLA2‐activated neurons was strikingly increased after peripheral nerve injury but not after peripheral inflammation produced by complete Freund’s adjuvant. Pharmacological blockade of P2X3R/P2X2/3R reversed the nerve injury‐induced cPLA2 activation in DRG neurons. Moreover, administering the cPLA2 inhibitor near the DRG suppressed nerve injury‐induced tactile allodynia, a hallmark of neuropathic pain. Our results suggest that P2X3R/P2X2/3R‐dependent cPLA2 activity in primary sensory neurons is a key event in neuropathic pain and that cPLA2 might be a potential target for treating neuropathic pain.