吗啡外周镇痛依赖于 PI3Kγ/AKT/nNOS/NO/KATP 信号通路的激活。
Morphine peripheral analgesia depends on activation of the PI3Kgamma/AKT/nNOS/NO/KATP signaling pathway.
机构信息
Department of Pharmacology, Faculty of Medicine, Ribeirão Preto University of São Paulo, Ribeirão Preto, 14049-900 São Paulo, Brazil.
出版信息
Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4442-7. doi: 10.1073/pnas.0914733107. Epub 2010 Feb 10.
Abstract
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 PI3Kgamma/AKT protein kinase B (AKT) and culminated in increased activation 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.
摘要
吗啡是一种被广泛应用于治疗急性和慢性疼痛的处方药物，具有显著的疗效。除了中枢镇痛作用外，吗啡还具有外周镇痛作用。然而，吗啡外周镇痛作用的机制尚未完全阐明。本研究表明，神经元型一氧化氮合酶敲除小鼠对吗啡的外周镇痛作用丧失，且吗啡可诱导初级伤害感受神经元产生一氧化氮。吗啡诱导的一氧化氮通路激活依赖于对 PI3Kγ/蛋白激酶 B（AKT）的初始刺激，最终导致 KATP 通道的激活。在后者中，这种细胞内信号通路可能导致伤害性神经元的超极化，这对于吗啡直接阻断炎症性疼痛至关重要。这一发现为开发新型镇痛药物提供了新的靶点。
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