Pajohanfar Nasim Sadat, Mohebbi Ehsan, Hosseini-Bandegharaei Ahmad, Amin Mohamadraza, Vaseghi Golnaz, Amin Bahareh
Student Research Committee, Sabzevar University of Medical Sciences, Sabzevar, Iran.
Department of Environmental Health Engineering, School of Public Health, Sabzevar University of Medical Sciences, Sabzevar, Iran; Department of Engineering, Kashmar Branch, Islamic Azad University, PO Box 161, Kashmar, Iran.
Biomed Pharmacother. 2017 Sep;93:406-411. doi: 10.1016/j.biopha.2017.06.054. Epub 2017 Jun 24.
Tolerance to analgesic effects of opioids and dependence to them are main concerns in the treatment of chronic pain conditions, limiting clinical application of these drugs. This study aimed to evaluate the effect of simvastatin on the morphine-induced tolerance and dependence in mice.
For this purpose, mice were treated with either daily morphine (20 mg/kg, s.c.) alone, or in combination with simvastatin (2.5, 5 and 10mg/kg, i.p.), for 9 continuous days. Antinociceptive effect of morphine was assessed through measuring latency time withdrawal of paw exposed to thermal stimulus, in the hot plate test. Naloxone-precipitated morphine withdrawal (5mg/kg, i.p.), was used for dependence evaluation. Changes in brain gene expression levels of induced nitric oxide synthase (iNOS), astroglia marker, glial fibrillary acidic protein (GFAP), ionized calcium-binding protein (Iba1) a microglia activation marker, a pro-inflammatory mediator and tumor necrosis alpha (TNF-α) were measured after withdrawal by real-time polymerase chain reaction (RT-PCR).
Behavioral tests indicated that latency time increased after morphine treatment in the hot plate test. However, this effect decreased on day 7, demonstrating tolerance to antinociceptive effect of morphine. Reduced anti-nociceptive effect of morphine was returned in animals treated with simvastatin (5 and 10mg/kg) in combination with morphine. Simvastatin (5 and 10mg/kg) attenuated morphine dependence as indicated by a less severe antagonist-precipitated withdrawal syndrome. Administration of naloxone was associated with the increased expression of TNF-α, GFAP, Iba1 and iNOS in the brain samples of morphine dependent mice, while the nine days treatment with both 5 and 10mg/kg simvastatin reduced such changes.
The obtained results showed that the protective effects of simvastatin against both tolerance to nociceptive effects of morphine as well as withdrawal-induced behavioral profile are meaningful. Inhibition of glia activity as well as antioxidant effects of pharmaceutical simvastatin further proves its neuroprotective property.
对阿片类药物镇痛作用的耐受性及其依赖性是慢性疼痛治疗中的主要问题，限制了这些药物的临床应用。本研究旨在评估辛伐他汀对小鼠吗啡诱导的耐受性和依赖性的影响。
为此，小鼠连续9天每日单独给予吗啡（20mg/kg，皮下注射），或与辛伐他汀（2.5、5和10mg/kg，腹腔注射）联合给药。通过在热板试验中测量暴露于热刺激的爪子的撤爪潜伏期时间来评估吗啡的抗伤害感受作用。用纳洛酮诱发的吗啡戒断反应（5mg/kg，腹腔注射）进行依赖性评估。撤药后通过实时聚合酶链反应（RT-PCR）测量脑内诱导型一氧化氮合酶（iNOS）、星形胶质细胞标志物胶质纤维酸性蛋白（GFAP）、小胶质细胞活化标志物离子钙结合蛋白（Iba1）、促炎介质肿瘤坏死因子α（TNF-α）的基因表达水平变化。
行为学测试表明，在热板试验中吗啡治疗后撤爪潜伏期时间增加。然而，这种作用在第7天减弱，表明对吗啡的抗伤害感受作用产生了耐受性。与吗啡联合使用的辛伐他汀（5和10mg/kg）治疗的动物中，吗啡降低的抗伤害感受作用恢复。辛伐他汀（5和10mg/kg）减轻了吗啡依赖性，表现为拮抗剂诱发的戒断综合征较轻。在吗啡依赖小鼠的脑样本中，给予纳洛酮与TNF-α、GFAP、Iba1和iNOS的表达增加有关，而5和10mg/kg辛伐他汀的9天治疗减少了这种变化。
所得结果表明，辛伐他汀对吗啡伤害感受作用耐受性以及戒断诱导行为特征均具有保护作用，这具有重要意义。药物辛伐他汀对神经胶质细胞活性的抑制作用以及抗氧化作用进一步证明了其神经保护特性。
