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Diclofenac-induced peripheral antinociception is associated with ATP-sensitive K+ channels activation

机译：双氯芬酸诱导的外周镇痛作用与ATP敏感的K +通道激活相关

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In order to investigate to the contribution of K+ channels on the peripheral antinociception induced by diclofenac, we evaluated the effect of several K+ channel blockers, using the rat paw pressure test, in which sensitivity is increased by intraplantar injection (2 mug) of prostaglandin E-2. Diclofenac administered locally into the right hindpaw (25, 50, 100 and 200 mug) elicited a dose-dependent antinociceptive effect which was demonstrated to be local, since only higher doses produced an effect when injected in the contralateral paw. This blockade of PGE(2) mechanical hyperalgesia induced by diclofenac (100 mug/paw) was antagonized in a dose-dependent manner by intraplantar administration of the sulphonylureas glibenclamide (40, 80 and 160 mug) and tolbutamide (80, 160 and 320 mug), specific blockers of ATP-sensitive K+ channels, and it was observed even when the hyperalgesic agent used was carrageenin, while the antinociceptive action of indomethacin (200 mug/ paw), a typical cyclo-oxygenase inhibitor, over carrageenin-induced hyperalgesia was not affected by this treatment. Charybdotoxin (2 mug/paw), a blocker of large conductance Ca2+-activated K+ channels and dequalinium (50 mug/paw), a selective blocker of small conductance Ca2+-activated K+ channels, did not modify the effect of diclofenac. This effect was also unaffected by intraplantar administration of non-specific voltage-dependent K+ channel blockers tetraethylammonium. (1700 mug) and 4-aminopyridine (100 mug) or cesium (500 mug), a non-specific K+ channel blocker. The peripheral antinociceptive effect induced. by diclofenac was antagonized by N-G-Nitro L-arginine (NOarg, 50 mug/paw), a NO synthase inhibitor and methylene blue (MB, 500 mug/paw), a guanylate cyclase inhibitor, and this antagonism was reversed by diazoxide (300 mug/paw), an ATP-sensitive K+ channel opener. We also suggest that an endogenous opioid system may not be involved since naloxone (50 mug/paw) did not affect diclofenac-induced antinociception in the PGE(2)-induced hyperalgesia model. This study provides evidence that the peripheral antinociceptive effect of diclofenac may result from activation of ATP-sensitive K+ channels, possible involving stimulation of L-arginine/NO/cGMP pathway, while Ca2+-activated K+ channels, voltage-dependent K+ channels as well as endogenous opioids appear not to be involved in the process. (C) 2004 Elsevier Inc. All rights reserved. [References: 41]
机译：为了研究K +通道对双氯芬酸诱导的外周镇痛作用的贡献，我们使用大鼠足压力试验评估了几种K +通道阻滞剂的作用，其中脚底注射前列腺素E可以提高敏感性（2杯） -2。双氯芬酸局部施用于右后爪（25、50、100和200马克杯）会引起剂量依赖性抗伤害感受，这种作用已被证明是局部的，因为当注射到对侧爪中时只有较高的剂量会产生作用。通过双足芬太尼格列本脲（40、80和160马克杯）和甲苯磺丁胺（80、160和320马克杯）intra内给药以剂量依赖的方式拮抗双氯芬酸（100杯/爪）诱导的PGE（2）机械痛觉过敏的拮抗作用。 ）是ATP敏感K +通道的特异性阻滞剂，即使在使用的止痛药是角叉菜胶的情况下也能观察到，而典型的环加氧酶抑制剂吲哚美辛（200杯/爪）的抗伤害感受作用优于角叉菜胶引起的痛觉过敏不受这种治疗的影响。 Charybdotoxin（2杯/爪），一种大电导的Ca2 +激活的K +通道的阻滞剂和dequalinium（50杯/爪），一种小电导的Ca2 +激活的K +通道的选择性阻滞剂，不会改变双氯芬酸的作用。脚底内施用非特异性电压依赖性K +通道阻滞剂四乙铵也不会影响该效果。 （1700杯）和4-氨基吡啶（100杯）或铯（500杯），一种非特定的K +通道阻滞剂。引起外周抗伤害感受作用。双氯芬酸的抗性被NG-硝基L-精氨酸（NOarg，50杯/爪），一氧化氮合酶抑制剂和亚甲基蓝（MB，500杯/爪），鸟苷酸环化酶抑制剂拮抗，这种拮抗作用被重氮（300杯子/爪子），一个对ATP敏感的K +通道开启器。我们还建议，由于纳洛酮（50杯/爪）在PGE（2）诱导的痛觉过敏模型中不影响双氯芬酸诱导的镇痛作用，因此可能不涉及内源性阿片类药物系统。这项研究提供的证据表明，双氯芬酸的外周镇痛作用可能是由于激活了ATP敏感的K +通道，可能涉及刺激L-精氨酸/ NO / cGMP途径，而Ca2 +激活的K +通道，电压依赖性K +通道以及内源性阿片类药物似乎不参与该过程。 （C）2004 Elsevier Inc.保留所有权利。 [参考：41]

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