Morphine peripheral analgesia depends on activation of the PI3Kγ/AKT/nNOS/NO/KATP signaling pathway
Morphine peripheral analgesia depends on activation of the PI3Kγ/AKT/nNOS/NO/KATP signaling pathway
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DOI：
10.1073/pnas.0914733107
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发表时间：
2010-03-02
影响因子：
11.1
通讯作者：
Ferreira, Sergio H.
中科院分区：
文献类型：
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作者：
Cunha, Thiago M.;Roman-Campos, Danilo;Ferreira, Sergio H.
吗啡是治疗急性和慢性疼痛的处方最多、最有效的药物之一。除中枢作用外，吗啡还能产生外周镇痛。然而，吗啡这种外周作用的机制尚未完全阐明。在这里，我们表明，在神经元性一氧化氮合酶缺失的小鼠中，吗啡的外周抗伤害性感受作用消失，并且吗啡诱导初级伤害感受性神经元产生一氧化氮。吗啡对一氧化氮通路的激活依赖于PI3K-Gamma/AKT蛋白激酶B(AKT)的初始刺激，最终导致K-ATP通道的激活。在后者中，这种细胞内信号通路可能引起伤害性神经元的超极化，是吗啡直接阻断炎性疼痛的基础。这一认识为止痛药的开发提供了新的靶点。
Morphine is one of the most prescribed and effective drugs used for the treatment of acute and chronic pain conditions. In addition to its central effects, morphine can also produce peripheral analgesia. However, the mechanisms underlying this peripheral action of morphine have not yet been fully elucidated. Here, we show that the peripheral antinociceptive effect of morphine is lost in neuronal nitric-oxide synthase null mice and that morphine induces the production of nitric oxide in primary nociceptive neurons. The activation of the nitric-oxide pathway by morphine was dependent on an initial stimulation of PI3K gamma/AKT protein kinase B (AKT) and culminated in increasedactivation of K-ATP channels. In the latter, this intracellular signaling pathway might cause a hyperpolarization of nociceptive neurons, and it is fundamental for the direct blockade of inflammatory pain by morphine. This understanding offers new targets for analgesic drug development.