Soleimanii Asma, Fallah Faezeh, Ghorbanzadeh Behnam, Oroojan Ali Akbar, Amirgholami Neda, Alboghobeish Soheila
School of medicine, Student Research Committee, Dezful University of Medical Sciences, Dezful, Iran.
Department of Pharmacology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran.
Pharmacol Biochem Behav. 2024 Dec;245:173864. doi: 10.1016/j.pbb.2024.173864. Epub 2024 Aug 30.
One of the reasons for tolerance to morphine is increased oxidative stress and dysfunction of cell mitochondria in the hippocampus. Venlafaxine and calcium channel blockers can protect mitochondrial function. The investigation of the role of mitochondrial damage and oxidative stress in the simultaneous use of venlafaxine and calcium channel blockers on the acute analgesic effects of morphine and the induction of tolerance to its effects in mice was assessed.
In this experimental study, to induce tolerance to morphine, NMRI mice were treated with 50 mg/kg morphine for three consecutive days and 5 mg/kg morphine on the fourth day. Venlafaxine (20 mg/kg) alone or in combination with calcium channel blockers, nimodipine (10 mg/kg), and diltiazem (40 mg/kg) was administered 30 min before morphine, and the hot plate test was used. Then, hippocampal mitochondria were isolated by differential centrifugation method, and the levels of mitochondrial dehydrogenase activity, mitochondrial membrane potential, mitochondrial ROS production rate, as well as the content of glutathione and malondialdehyde in hippocampal mitochondria, were measured.
The administration of venlafaxine-nimodipine and venlafaxine-diltiazem increased morphine's acute analgesic effects (P < 0.05) and reduced the induction and expression of tolerance to the analgesic effects of morphine (P < 0.05). Morphine significantly decreased MTT and GSH and increased MDA, mitochondrial membrane damage, and ROS compared to the control group (P < 0.01). Injection of venlafaxine-nimodipine and also venlafaxine-diltiazem 30 min before morphine can improve these alterations (P < 0.05).
Our data showed that the simultaneous use of venlafaxine with calcium channel blockers could increase the acute analgesic effects of morphine and reduce the induction and expression of tolerance to it. Also, the preventive and protective roles of simultaneous administration of venlafaxine and calcium channel blockers on morphine-induced mitochondrial oxidative stress and damage during the tolerance test were achieved.
对吗啡产生耐受性的原因之一是海马体中氧化应激增加以及细胞线粒体功能障碍。文拉法辛和钙通道阻滞剂可以保护线粒体功能。本研究评估了线粒体损伤和氧化应激在同时使用文拉法辛和钙通道阻滞剂对吗啡急性镇痛作用及诱导小鼠对其产生耐受性中的作用。
在本实验研究中，为诱导小鼠对吗啡产生耐受性，NMRI小鼠连续三天接受50mg/kg吗啡治疗，第四天接受5mg/kg吗啡治疗。在注射吗啡前30分钟单独给予文拉法辛（20mg/kg）或与钙通道阻滞剂尼莫地平（10mg/kg）和地尔硫䓬（40mg/kg）联合给药，并采用热板试验。然后，通过差速离心法分离海马体线粒体，测量线粒体脱氢酶活性、线粒体膜电位、线粒体活性氧产生率以及海马体线粒体中谷胱甘肽和丙二醛的含量。
文拉法辛 - 尼莫地平和文拉法辛 - 地尔硫䓬联合给药增加了吗啡的急性镇痛作用（P<0.05），并降低了对吗啡镇痛作用耐受性的诱导和表达（P<0.05）。与对照组相比，吗啡显著降低了MTT和GSH水平，增加了MDA、线粒体膜损伤和ROS（P<0.01）。在吗啡注射前30分钟注射文拉法辛 - 尼莫地平和文拉法辛 - 地尔硫䓬可改善这些变化（P<0.05）。
我们的数据表明，文拉法辛与钙通道阻滞剂同时使用可增加吗啡的急性镇痛作用，并降低对其耐受性的诱导和表达。此外，在耐受性试验期间，文拉法辛和钙通道阻滞剂同时给药对吗啡诱导的线粒体氧化应激和损伤具有预防和保护作用。
