Ghavimi Hamed, Hassanzadeh Kambiz, Maleki-Dizaji Nasrin, Azarfardian Alireza, Ghasami Saeed, Zolali Elmira, Charkhpour Mohammad
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Naunyn Schmiedebergs Arch Pharmacol. 2014 Sep;387(9):811-21. doi: 10.1007/s00210-014-0996-y. Epub 2014 Jun 5.
Long-term exposure to opiates induces tolerance to the analgesic effect and dependence. The purpose of the present study is to investigate the effects of pioglitazone, a peroxisome proliferator-activated receptors gamma (PPAR-γ) agonist, on the morphine-induced tolerance and dependence. Groups of rats received morphine in combination with a vehicle or pioglitazone (5, 10, 20, and 40 mg/kg) daily. Thirty minutes before pioglitazone (40 mg/kg), GW-9662, a selective PPAR-γ antagonist, (2 mg/kg) was administrated in order to evaluate the possible role of the PPAR-γ. Nociception was assessed by a tail flick apparatus, and the percentage of the maximal possible effect was calculated as well. For 9 days, rats received additive doses of morphine to induce dependence. Naloxone was administrated 2 h after the morphine last dose, and withdrawal symptoms were recorded for 45 min. Morphine administration to rats over a duration of 17 days resulted in the development of tolerance, whereas pioglitazone (40 mg/kg) delayed the day of the established tolerance for 15 days. Administration of pioglitazone also prevented morphine-induced 50 % effective dose (ED50) shift to the right in the dose-response curve and increased the global analgesic effect of morphine. In addition, pioglitazone decreased the total withdrawal score significantly, whereas GW-9662 significantly reversed the pioglitazone effects on the morphine tolerance and dependence. The prevention of the morphine-induced glia activation and the proinflammatory responses were the possible mechanisms for pioglitazone effect on delaying the morphine tolerance and attenuating the dependence.
长期接触阿片类药物会导致对镇痛作用产生耐受性和依赖性。本研究的目的是调查过氧化物酶体增殖物激活受体γ（PPAR-γ）激动剂吡格列酮对吗啡诱导的耐受性和依赖性的影响。将大鼠分组，每天给予吗啡并同时给予赋形剂或吡格列酮（5、10、20和40mg/kg）。在给予吡格列酮（40mg/kg）前30分钟，给予选择性PPAR-γ拮抗剂GW-9662（2mg/kg），以评估PPAR-γ的可能作用。通过甩尾装置评估伤害感受，并计算最大可能效应的百分比。连续9天，给予大鼠递增剂量的吗啡以诱导依赖性。在末次给予吗啡2小时后给予纳洛酮，并记录45分钟的戒断症状。对大鼠连续17天给予吗啡导致耐受性形成，而吡格列酮（40mg/kg）使耐受性确立的时间推迟了15天。给予吡格列酮还可防止吗啡诱导的剂量反应曲线中50%有效剂量（ED50）右移，并增强吗啡的整体镇痛效果。此外，吡格列酮显著降低了总的戒断评分，而GW-9662显著逆转了吡格列酮对吗啡耐受性和依赖性的作用。吡格列酮预防吗啡诱导的胶质细胞激活和促炎反应可能是其延迟吗啡耐受性和减轻依赖性的作用机制。
