Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, PO 80260, Jeddah, 21589, Saudi Arabia; Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Fundam Clin Pharmacol. 2013 Dec;27(6):623-31. doi: 10.1111/fcp.12004. Epub 2012 Oct 3.
This study investigated the role of K(ATP) channels in morphine-induced antinociception and hepatic oxidative stress in acute and inflammatory pain. The K(ATP) channel modulators (K(ATP) channel opener, diazoxide 100 mg/kg, p.o, and K(ATP) channel blocker, glibenclamide, 3 mg/kg i.p.) were administered with morphine (80 mg/kg, i.p.). Antinociception was assessed by the tail-flick and formalin tests in rats and measured by the area under the curve values and the maximum percent effect for 3 h. The indices of hepatic oxidative stress: glutathione, glutathione peroxidase, and malondialdehyde were then determined in the liver homogenates obtained from the treated animals. In both tests, glibenclamide antagonized morphine-induced antinociception, whereas diazoxide augmented it in the tail-flick test only. In the formalin test, glibenclamide alone has a significant hyperalgesic effect, whereas diazoxide decreased the number of flinches. Coadministration of glibenclamide with morphine antagonized the hepatotoxic effect of morphine in both animal models. In the tail-flick test, glibenclamide administered alone significantly increased malondialdehyde's level. Coadministration of diazoxide with morphine increased glutathione level in the formalin test. Diazoxide administered alone exacerbated the hepatic oxidative stress in both animal models. These findings suggest a role of K(ATP) channel modulators on morphine-induced antinociception and hepatic oxidative stress. The administration of glibenclamide may prevent morphine-induced hepatotoxicity. The effectiveness of diazoxide in the management of pain is limited due to its deleterious effect on the liver. However, the interaction of the K(ATP) channel modulators with morphine depends on the differential sensitivity to the pain stimulus.
这项研究探讨了 K(ATP) 通道在吗啡诱导的镇痛作用和急性及炎症性疼痛中的肝氧化应激中的作用。K(ATP) 通道调节剂（K(ATP) 通道开放剂，二氮嗪 100mg/kg，po，和 K(ATP) 通道阻滞剂，格列本脲，3mg/kg，ip）与吗啡（80mg/kg，ip）一起给药。通过对大鼠的尾部闪烁和福尔马林试验来评估镇痛作用，并通过曲线下面积值和 3 小时内的最大百分效应来测量。然后在从处理过的动物获得的肝匀浆中测定肝氧化应激的指标：谷胱甘肽、谷胱甘肽过氧化物酶和丙二醛。在这两种试验中，格列本脲拮抗吗啡诱导的镇痛作用，而二氮嗪仅在尾部闪烁试验中增强它。在福尔马林试验中，格列本脲本身具有显著的痛觉过敏作用，而二氮嗪则减少了抽搐次数。格列本脲与吗啡共同给药拮抗了两种动物模型中吗啡的肝毒性作用。在尾部闪烁试验中，格列本脲单独给药显著增加了丙二醛的水平。二氮嗪与吗啡共同给药增加了福尔马林试验中的谷胱甘肽水平。二氮嗪单独给药加剧了两种动物模型中的肝氧化应激。这些发现表明 K(ATP) 通道调节剂对吗啡诱导的镇痛作用和肝氧化应激具有作用。给予格列本脲可能预防吗啡引起的肝毒性。由于二氮嗪对肝脏的有害作用，其在疼痛管理中的有效性受到限制。然而，K(ATP) 通道调节剂与吗啡的相互作用取决于对疼痛刺激的不同敏感性。
