Role of P2X7 Receptor-Mediated IL-18/IL-18R Signaling in Morphine Tolerance: Multiple Glial-Neuronal Dialogues in the Rat Spinal Cord
Role of P2X7 Receptor-Mediated IL-18/IL-18R Signaling in Morphine Tolerance: Multiple Glial-Neuronal Dialogues in the Rat Spinal Cord
复制标题
P2X7 受体介导的 IL-18/IL-18R 信号转导在吗啡耐受中的作用：大鼠脊髓中的多个胶质神经元对话
DOI：
10.1016/j.jpain.2012.06.007
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发表时间：
2012-10-01
期刊：
影响因子：
4
通讯作者：
Zhao, Zhi-Qi
中科院分区：
文献类型：
--
作者：
Chen, Meng-Ling;Cao, Hong;Zhao, Zhi-Qi
神经胶质细胞在吗啡耐受中的作用已被探讨，但其机制尚不清楚。我们之前的研究表明，小胶质细胞表达的P2X7受体（P2X7R）有助于诱导大鼠对吗啡镇痛的耐受。本研究进一步探讨了P2X7R在吗啡耐受中的潜在下游机制。结果显示，P2X7R拮抗剂或靶向小干扰RNA （siRNA）阻断P2X7受体可降低小鼠疼痛行为测试、体内脊髓细胞外记录和体外脊髓切片全细胞记录对吗啡镇痛的耐受性。慢性吗啡治疗分别引起小胶质细胞白介素(IL)-18、星形胶质细胞IL-18受体（IL- 18r）和脊髓背角神经元蛋白激酶C γ (PKC γ)的表达增加，这些表达被P2X7R拮抗剂或靶向siRNA阻断。慢性吗啡治疗也诱导脊髓星形胶质细胞d -丝氨酸释放增加。此外，d -氨基酸加氧酶（DAAO） （d -丝氨酸的降解酶）和双吲哚酰马来酰亚胺（BIM） （PKC抑制剂）都减弱了吗啡耐受性。本研究证明了吗啡耐受的脊髓机制，其中慢性吗啡通过涉及p2x7r - il -18- d -丝氨酸- n -甲基- d -天冬氨酸受体(NMDAR)-PKC γ介导的信号通路的级联触发脊髓胶质细胞和神经元细胞之间的多种对话。观点：本研究表明，脊髓中通过级联（p2x7r - il -18- d -丝氨酸- nmdar - pkc γ）的神经胶质细胞相互作用在吗啡耐受中起重要作用。这篇文章可能为慢性疼痛临床治疗中预防吗啡镇痛耐受提供了潜在的新治疗靶点。(C) 2012年由美国疼痛学会出版
The glial function in morphine tolerance has been explored, but its mechanisms remain unclear. Our previous study has showed that microglia-expressed P2X7 receptors (P2X7R) contribute to the induction of tolerance to morphine analgesia in rats. This study further explored the potential downstream mechanisms of P2X7R underlying morphine tolerance. The results revealed that the block-ade of P2X7 receptor by P2X7R antagonist or targeting small interfering RNA (siRNA) reduced tolerance to morphine analgesia in the pain behavioral test and spinal extracellular recordings in vivo and whole-cell recording of the spinal cord slice in vitro. Chronic morphine treatment induced an increase in the expression of interleukin (IL)-18 by microglia, IL-18 receptor (IL-18R) by astrocytes, and protein kinase C gamma (PKC gamma) by neurons in the spinal dorsal horn, respectively, which was blocked by a P2X7R antagonist or targeting siRNA. Chronic morphine treatment also induced an increased release of D-serine from the spinal astrocytes. Further, both D-amino acid oxygenase (DAAO), a degrading enzyme of D-serine, and bisindolylmaleimide alpha (BIM), a PKC inhibitor, attenuated morphine tolerance. The present study demonstrated a spinal mechanism underlying morphine tolerance, in which chronic morphine triggered multiple dialogues between glial and neuronal cells in the spinal cord via a cascade involving a P2X7R-IL-18-D-serine-N-methyl-D-aspartate receptor (NMDAR)-PKC gamma-mediated signaling pathway. Perspective: The present study shows that glia-neuron interaction via a cascade (P2X7R-IL-18-D-serine-NMDAR-PKC gamma) in the spinal cord plays an important role in morphine tolerance. This article may represent potential new therapeutic targets for preventing morphine analgesic tolerance in clinical management of chronic pain. (C) 2012 by the American Pain Society