Mansouri Mohammad Taghi, Khodayar Mohammad Javad, Tabatabaee Amirhossein, Ghorbanzadeh Behnam, Naghizadeh Bahareh
Department of Pharmacology, School of Medicine, Ahvaz Jundishapur Univ. of Med. Sciences, Ahvaz, Iran.
Department of Toxicology and Pharmacology, School of Pharmacy, Ahvaz Jundishapur Univ. of Med. Sciences, Ahvaz, Iran.
Pharmacol Biochem Behav. 2015 Oct;137:38-43. doi: 10.1016/j.pbb.2015.08.002. Epub 2015 Aug 6.
Statins, 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors, are widely used in the management of different diseases beyond their primary indication for lowering cholesterol. Previous studies have demonstrated the neuroprotective effects of simvastatin in different animal models. In the present study, we examined the effects of simvastatin (30, 60, 100 and 300mg/kg, p.o.) on the development and expression of morphine-induced tolerance and dependence in mice. For the induction of morphine tolerance and dependence, mice were twice daily treated with morphine (10mg/kg, s.c.) for 5 consecutive days. Tolerance was evaluated by the hot-plate test and physical dependence by naloxone challenge, on the sixth day. The results showed that oral administration of simvastatin produced antinociceptive activity in a dose-dependent way. Co-administration of simvastatin with morphine did not affect the acute morphine-induced analgesia (10mg/kg, s.c.). However, repeated co-administration of simvastatin with morphine significantly attenuated the development of tolerance to the analgesic effect of morphine and inhibited the naloxone (5mg/kg, s.c.)-precipitated withdrawal signs (jumping and body weight loss). Also, simvastatin at doses of 100 and 300mg/kg attenuated the expression of morphine-induced tolerance and dependence. These data indicated that, while simvastatin can alleviate both development and expression of morphine-induced tolerance, it cannot enhance morphine-induced antinociception. Taken together, simvastatin may be used as an adjutant therapeutic agent in combination with morphine and or other opioids in patients with severe chronic pain.
他汀类药物，即3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，除了用于降低胆固醇这一主要适应证外，还广泛应用于不同疾病的治疗。先前的研究已证实辛伐他汀在不同动物模型中具有神经保护作用。在本研究中，我们检测了辛伐他汀（30、60、100和300mg/kg，口服）对小鼠吗啡诱导的耐受性和依赖性的产生及表达的影响。为诱导小鼠产生吗啡耐受性和依赖性，连续5天每天两次给小鼠皮下注射吗啡（10mg/kg）。在第6天，通过热板试验评估耐受性，通过纳洛酮激发试验评估身体依赖性。结果显示，口服辛伐他汀产生剂量依赖性的抗伤害感受活性。辛伐他汀与吗啡联合给药不影响急性吗啡诱导的镇痛作用（10mg/kg，皮下注射）。然而，辛伐他汀与吗啡重复联合给药显著减弱了对吗啡镇痛作用的耐受性的产生，并抑制了纳洛酮（5mg/kg，皮下注射）诱发的戒断症状（跳跃和体重减轻）。此外，100和300mg/kg剂量的辛伐他汀减弱了吗啡诱导的耐受性和依赖性的表达。这些数据表明，虽然辛伐他汀可以减轻吗啡诱导的耐受性的产生和表达，但它不能增强吗啡诱导的抗伤害感受作用。综上所述，辛伐他汀可作为辅助治疗药物与吗啡和/或其他阿片类药物联合用于重度慢性疼痛患者。
