P2X7-dependent release of interleukin-1beta and nociception in the spinal cord following lipopolysaccharide.
P2X7-dependent release of interleukin-1beta and nociception in the spinal cord following lipopolysaccharide.
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DOI：
10.1523/jneurosci.3295-09.2010
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发表时间：
2010-01-13
期刊：
影响因子：
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通讯作者：
Malcangio M
中科院分区：
文献类型：
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作者：
Clark AK;Staniland AA;Marchand F;Kaan TK;McMahon SB;Malcangio M
脊髓小胶质细胞在增强反应状态下释放的细胞因子白细胞介素-1 β（IL-1β）在慢性疼痛的神经机制中起重要作用。在这里，我们研究了嘌呤能P2 X7受体在背角Toll样受体4（TLR 4）激活后IL-1β释放中的参与，这与伤害性行为和小胶质细胞激活有关。我们观察到LPS诱导的IL-1β释放被A-438079对P2 X7受体的药理学抑制所阻止，并且在取自P2 X7敲除小鼠的脊髓切片中不存在。应用ATP并不引起从背角释放IL-1β，除非在LPS引发刺激之前，并且这种释放依赖于P2 X7受体激活。发现背角小胶质细胞中p38 MAPK的广泛磷酸化与LPS和ATP后的IL-1β分泌相关。在行为研究中，在腰髓鞘内注射LPS在大鼠后爪中产生机械性痛觉过敏，其通过同时注射非特异性（氧化ATP）或特异性（A-438079）P2 X7拮抗剂而减弱。此外，在野生型小鼠中观察到LPS诱导的超敏反应，但在P2 X7敲除小鼠中未观察到。这些数据表明P2 X7受体在与背角中小胶质细胞活化和IL-1β分泌相关的增强的伤害性传递中起关键作用。我们认为，中枢神经系统渗透剂P2 X7受体拮抗剂，通过靶向疼痛增强反应状态的小胶质细胞，可能有利于治疗持续性疼痛。
The cytokine Interleukin-1β (IL-1β) released by spinal microglia in enhanced response states contributes significantly to neuronal mechanisms of chronic pain. Here we examine the involvement of the purinergic P2X7 receptor in the release of IL-1β following activation of Toll-like receptor-4 (TLR4) in the dorsal horn, which is associated with nociceptive behaviour and microglial activation. We observed that LPS induced release of IL-1β was prevented by pharmacological inhibition of the P2X7 receptor with A-438079, and was absent in spinal cord slices taken from P2X7 knock-out mice. Application of ATP did not evoke release of IL-1β from the dorsal horn unless preceded by an LPS priming stimulus, and this release was dependent on P2X7 receptor activation. Extensive phosphorylation of p38 MAPK in microglial cells in the dorsal horn was found to correlate with IL-1β secretion following both LPS and ATP. In behavioural studies, intrathecal injection of LPS in the lumbar spinal cord produced mechanical hyperalgesia in rat hind-paws which was attenuated by concomitant injections of either a non-specific (oxidized ATP) or a specific (A-438079) P2X7 antagonist. In addition, LPS induced hypersensitivity was observed in wild-type, but not P2X7 knock-out mice. These data suggest a critical role for the P2X7 receptor in the enhanced nociceptive transmission associated with microglial activation and secretion of IL-1β in the dorsal horn. We suggest that CNS penetrant P2X7 receptor antagonists, by targeting microglia in pain-enhanced response states, may be beneficial for the treatment of persistent pain.