Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl⁻ homeostasis.
Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl⁻ homeostasis.
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DOI：
10.1038/nn.3295
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发表时间：
2013-02
影响因子：
25
通讯作者：
De Koninck Y
中科院分区：
文献类型：
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作者：
Ferrini F;Trang T;Mattioli TA;Laffray S;Del'Guidice T;Lorenzo LE;Castonguay A;Doyon N;Zhang W;Godin AG;Mohr D;Beggs S;Vandal K;Beaulieu JM;Cahill CM;Salter MW;De Koninck Y
治疗疼痛的一个主要未解决的问题是由黄金标准镇痛吗啡和其他阿片类药物产生的矛盾性痛觉过敏。我们发现吗啡引起的痛觉过敏导致K +-Cl −协同转运蛋白KCC2的下调，损害了脊髓1层神经元中Cl −的稳态。恢复Eanion逆转吗啡诱导的痛觉过敏，而不影响耐受性。切除脊髓小胶质细胞也可逆转痛觉过敏。吗啡痛觉过敏（而非耐受）需要小胶质细胞中μ阿片受体依赖性P2X4受体（P2X4Rs）的表达和P2X4Rs对脑源性神经营养因子（BDNF）释放的μ非依赖性门控。阻断BDNF-TrkB信号传导可以保持Cl −稳态并逆转痛觉过敏。从小胶质细胞中删除BDNF的基因靶向小鼠不会对吗啡产生痛觉过敏。然而，在这些动物中，吗啡抗伤害感受和耐受性都没有受到影响。我们的发现将吗啡诱导的痛觉过敏与耐受分离，并揭示了小胶质细胞-神经元P2X4-BDNF-KCC2通路作为治疗靶点，以防止痛觉过敏而不影响吗啡镇痛。
A major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opiates. We show here that hyperalgesia-inducing treatment with morphine causes downregulation of the K+-Cl− cotransporter KCC2, impairing Cl− homeostasis in spinal lamina l neurons. Restoring Eanion reversed the morphine-induced hyperalgesia without affecting tolerance. The hyperalgesia was also reversed by ablating spinal microglia. Morphine hyperalgesia, but not tolerance, required μ opioid receptor-dependent expression of P2X4 receptors (P2X4Rs) in microglia and μ-independent gating of the release of brain-derived neurotrophic factor (BDNF) by P2X4Rs. Blocking BDNF-TrkB signalling preserved Cl− homeostasis and reversed the hyperalgesia. Gene-targeted mice in which BDNF was deleted from microglia did not develop hyperalgesia to morphine. Yet, neither morphine antinociception nor tolerance was affected in these animals. Our findings dissociate morphine-induced hyperalgesia from tolerance and unveil the microglia-to-neuron P2X4-BDNF-KCC2 pathway as a therapeutic target to prevent hyperalgesia without affecting morphine analgesia.