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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Peripheral analgesic blockade of hypernociception: Activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K+ channel pathway
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Peripheral analgesic blockade of hypernociception: Activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K+ channel pathway

机译：痛觉过敏的外周镇痛阻滞剂：精氨酸/ NO / cGMP /蛋白激酶G / ATP敏感性K +通道途径的激活

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摘要

The final step in the direct restoration of the nociceptor threshold by peripheral administration of morphine and dipyrone was recently suggested to result from the opening of ATP-sensitive K+ channels (K-ATP(+)). This channel is known to be open either directly by cGMP or indirectly via protein kinase G (PKG) stimulation. In the present study, it was shown that the blockade was caused by a specific PKG inhibitor (KT5823) of the antinociceptive effect of morphine and dipyrone on acute hypernociception and of dipyrone on persistent hypernociception. It was also shown that, in both models, KT5823 prevented the peripheral antinociceptive effect of an analogue of cGMP, the nitric oxide (NO) donor (S-nitroso-N-acetyl-D,L-penicilamine). However, in acute hypernociception, KT5823 did not prevent the peripheral antinociceptive effect of diazoxide (a direct K-ATP(+) opener). In persistent hypernociception, the sensitization plateau was induced by daily injections of prostaglandin E-2 (PGE(2), 100 ng) into the rat paw for 14 days. After cessation of PGE(2) injections, the pharmacological blockade of persistent hypernociception led to a quiescent phase in which a rather small stimulus restored the hypernociceptive plateau. In this phase, glibenclamide (which specifically closes K-ATP(+)) fully restored persistent hypernociception, as did injection of PGE(2). Thus, the activation of the arginine/NO/cGMP pathway causes direct blockade of acute and persistent hypernociception by opening K-ATP(+) via the stimulation of PKG. Analgesic stimulators of the neuronal arginine/NO/cGMP/PKG/K-ATP(+) pathway constitute a previously undescribed well defined class of peripheral analgesics with a mechanism of action different from either glucocorticoids or inhibitors of cyclooxygenases. [References: 69]
机译：最近建议通过外围施用吗啡和双嘧啶来直接恢复伤害感受器阈值的最后一步是由于打开了ATP敏感的K +通道（K-ATP（+））。已知该通道可以通过cGMP直接打开，也可以通过蛋白激酶G（PKG）间接打开。在本研究中，显示出该阻断作用是由一种特定的PKG抑制剂（KT5823）引起的，该抑制剂对吗啡和双嘧啶对急性痛觉过敏的镇痛作用和双嘧啶对持续性痛觉过敏的镇痛作用。还显示出，在两个模型中，KT5823都可防止cGMP类似物（一氧化氮（NO）供体）（S-亚硝基-N-乙酰基-D，L-青霉胺）的外周镇痛作用。但是，在急性痛觉过敏中，KT5823不能阻止二氮嗪（直接的K-ATP（+）开放剂）的外周镇痛作用。在持续性痛觉过敏中，每天向大鼠爪内注射前列腺素E-2（PGE（2），100 ng）可以诱发致敏期。停止PGE（2）注射后，持续性痛觉超敏反应的药理学阻断作用导致一个静止期，在此阶段，相当小的刺激恢复了痛觉超敏的高原。在这个阶段，格列苯脲（特别是关闭K-ATP（+））完全恢复了持续性痛觉过敏，注射PGE（2）也是如此。因此，精氨酸/ NO / cGMP途径的激活通过经由PKG的刺激打开K-ATP（+），导致急性和持续性高伤害感受的直接阻断。神经元精氨酸/ NO / cGMP / PKG / K-ATP（+）途径的镇痛刺激物构成了一种以前未明确定义的外周镇痛药，其作用机理与糖皮质激素或环氧合酶抑制剂不同。 [参考：69]

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