Alves Daniela P, Soares Adriana C, Francischi Janetti N, Castro Maria S A, Perez Andréa C, Duarte Igor D G
Department of Pharmacology, Institute of Biological Sciences, UFMG, Av. Antônio Carlos, 6622-Campus da Pampulha, CEP 31.270.100, Belo Horizonte MG, Brazil.
Eur J Pharmacol. 2004 Apr 5;489(1-2):59-65. doi: 10.1016/j.ejphar.2004.02.022.
Using the rat paw pressure test, in which increased sensitivity is induced by intraplantar injection of prostaglandin E2, we assessed the antinociceptive effect of the ATP-sensitive K+ channel opener diazoxide and the large-conductance Ca(2+)-activated K+ channel opener NS-1619 (1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl) phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one) on the peripheral hyperalgesia induced by prostaglandin E2. Diazoxide, administered locally into the right hindpaw (20, 38, 75, 150, 300 and 600 microg), elicited a dose-dependent antinociceptive effect on prostaglandin E2-induced hyperalgesia (2 microg/paw). The effect of diazoxide at the dose of 300 microg/paw was shown to be local since it did not produce any effect when administered in the contralateral paw. The action of diazoxide (300 microg/paw) as an ATP-sensitive K+ channel opener seems to be specific, since its effect was antagonized in a dose-dependent manner by glibenclamide (40, 80 and 160 microg/paw), a specific blocker of these channels, while tetraethylammonium (7.5, 15 and 30 microg/paw), dequalinium (12.5, 25 and 50 microg/paw) or charybdotoxin (0.5, 1 and 2 microg/paw), blockers of voltage-dependent K+ channels and of small- and large-conductance Ca(2+)-activated K+ channels, respectively, were not able to abolish the antinociception induced by diazoxide. The peripheral antinociceptive effect of diazoxide was not prevented by prior administration of naloxone (12.5, 25 and 50 microg/paw), an opioid receptor antagonist, or methylene blue (75, 125 and 300 microg/paw), an agent that inhibits the activation of guanylate cyclase by nitric oxide. A low dose of diazoxide (20 microg/paw) administered together with a low dose of sodium nitroprusside (125 microg/paw) or dibutyryl cGMP (db-cGMP, 50 microg/paw) induced a marked antinociceptive effect similar to that observed when each drug was administered alone. NS1619 (75, 150 and 300 microg/paw), a specific opener of large-conductance Ca(2+)-activated K+ channels, had no antinociceptive action on prostaglandin E2-induced hyperalgesia. This series of experiments provides evidence for a peripheral antinociceptive action of diazoxide and supports the suggestion that the activation of ATP-sensitive K+ channels could be the mechanism by which sodium nitroprusside and db-cGMP induce peripheral antinociception, excluding the involvement of large-contuctance Ca(2+)-activated K+ channels in the process.
采用大鼠足爪压力试验，通过足底注射前列腺素E2诱导敏感性增加，我们评估了ATP敏感性钾通道开放剂二氮嗪和大电导钙激活钾通道开放剂NS - 1619（1,3 - 二氢 - 1 - [2 - 羟基 - 5 -（三氟甲基）苯基] - 5 -（三氟甲基）- 2H - 苯并咪唑 - 2 - 酮）对前列腺素E2诱导的外周痛觉过敏的镇痛作用。将二氮嗪局部注射到右后爪（20、38、75、150、300和600微克），对前列腺素E2诱导的痛觉过敏（2微克/爪）产生剂量依赖性镇痛作用。300微克/爪剂量的二氮嗪的作用显示为局部性的，因为当注射到对侧爪时未产生任何作用。300微克/爪剂量的二氮嗪作为ATP敏感性钾通道开放剂的作用似乎具有特异性，因为其作用被格列本脲（40、80和160微克/爪）以剂量依赖性方式拮抗，格列本脲是这些通道的特异性阻滞剂，而四乙铵（7.5、15和30微克/爪）、地喹氯铵（12.5、25和50微克/爪）或蝎毒素（0.5、1和2微克/爪），分别为电压依赖性钾通道以及小电导和大电导钙激活钾通道的阻滞剂，均不能消除二氮嗪诱导的镇痛作用。预先给予阿片受体拮抗剂纳洛酮（12.5、25和50微克/爪）或亚甲蓝（75、125和300微克/爪）（一种抑制一氧化氮激活鸟苷酸环化酶的药物）并不能阻止二氮嗪的外周镇痛作用。低剂量的二氮嗪（20微克/爪）与低剂量的硝普钠（125微克/爪）或二丁酰环磷鸟苷（db - cGMP，50微克/爪）一起给药诱导出明显的镇痛作用，类似于每种药物单独给药时观察到的作用。NS1619（75、150和300微克/爪），一种大电导钙激活钾通道的特异性开放剂，对前列腺素E2诱导的痛觉过敏没有镇痛作用。这一系列实验为二氮嗪的外周镇痛作用提供了证据，并支持以下观点：ATP敏感性钾通道的激活可能是硝普钠和db - cGMP诱导外周镇痛的机制，排除了大电导钙激活钾通道参与该过程。
