Acute methadone treatment reduces myocardial infarct size via the delta-opioid receptor in rats during reperfusion.
Acute methadone treatment reduces myocardial infarct size via the delta-opioid receptor in rats during reperfusion.
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DOI：
10.1213/ane.0b013e3181b92201
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发表时间：
2009-11
影响因子：
5.7
通讯作者：
Gross GJ
中科院分区：
文献类型：
--
作者：
Gross ER;Hsu AK;Gross GJ
美沙酮是一种阿片类激动剂，常用于治疗急性和慢性疼痛。我们试图确定美沙酮与吗啡相比是否剂量依赖性地减少心肌梗死面积（IS），以及其机制是否是δ-阿片受体介导的。此外，我们还研究了心肌IS减少是否随美沙酮给药时间或诱导缺血持续时间的变化而变化。手术置入后，将雄性Sprague-Dawley大鼠分为3组。第一组患者在缺血前30 min分别给予美沙酮（0.03-3 mg/kg）、吗啡（0.03-3 mg/kg）或水（安慰剂）治疗。第一组的一些动物在美沙酮（0.3 mg/kg）、吗啡（0.3 mg/kg）或安慰剂之前还接受了δ-阿片类拮抗剂纳曲多（5 mg/kg）。第二组动物分为再灌注前5 min和再灌注后10 s给予美沙酮（0.3 mg/kg）治疗组。两组大鼠均经冠状动脉左前降支阻断心肌缺血30 min，再灌注2 h。第三组动物在再灌注前5分钟给予安慰剂、美沙酮（0.3 mg/kg）或吗啡（0.3 mg/kg），左冠状动脉前降支闭塞缺血45 min，再灌注2 h。心肌IS通过三苯四唑氯染色心肌组织来评估，并以危险面积的百分比表示（平均值±sem）。缺血前给予美沙酮或吗啡降低心肌IS。在0.3 mg/kg剂量下达到最大效果（美沙酮为46%±1%，P < 0.001，吗啡为47%±1%，P < 0.001，安慰剂为61%±1%）。纳曲多（5mg /kg）阻断美沙酮诱导（0.3 mg/kg）和吗啡诱导（0.3 mg/kg）的心脏保护作用（纳曲多+美沙酮，58%±1%，与美沙酮相比P < 0.001；纳曲多+吗啡，58±1%，与吗啡相比P < 0.001）。美沙酮（0.3 mg/kg）在再灌注前5分钟给予可降低心肌IS(46%±1%，与安慰剂相比P < 0.001)，但在再灌注后10秒没有降低心肌IS（60%±1%，与安慰剂相比P = 0.675）。45 min缺血组（64%±1%）与30 min缺血组（60%±1%,P = 0.069）比较，安慰剂组心肌IS无显著差异。较长的45min缺血时间消除了美沙酮诱导的IS减少（64%±2%,P = 0.867，相比45min缺血安慰剂组）和吗啡诱导的IS减少（65%±1%,P = 0.836，相比45min缺血安慰剂组）。这些结果表明，美沙酮和吗啡产生类似的心肌is保留作用，这种作用是由δ阿片受体介导的，并依赖于心肌缺血的持续时间。
Methadone is an opioid agonist often given to manage acute and chronic pain. We sought to determine whether methadone compared with morphine dose dependently reduces myocardial infarct size (IS) and whether the mechanism is δ-opioid receptor mediated. Furthermore, we examined whether myocardial IS reduction varies with the timing of methadone administration or duration of induced ischemia. After surgical instrumentation, we divided male Sprague-Dawley rats into 3 sets. The first set was divided into groups, which received methadone (0.03–3 mg/kg), morphine (0.03–3 mg/kg), or water (placebo) 30 min before ischemia. Some animals of the first set also received the δ-opioid antagonist naltrindole (5 mg/kg) before methadone (0.3 mg/kg), morphine (0.3 mg/kg), or placebo administration. The second set of animals was divided into groups that received methadone (0.3 mg/kg) 5 min before reperfusion or 10 s after reperfusion. These 2 sets of animals were subjected to 30 min of myocardial ischemia by left anterior descending coronary artery occlusion and then 2 h of reperfusion. The third set of animals received placebo, methadone (0.3 mg/kg), or morphine (0.3 mg/kg) 5 min before reperfusion and were subjected to 45 min of ischemia by left anterior descending coronary artery occlusion with 2 h of reperfusion. Myocardial IS was assessed by staining myocardial tissue with triphenyltetrazolium chloride and expressed as a percentage of the area at risk (mean ± sem). Methadone or morphine administered before ischemia reduced myocardial IS. The greatest effect was achieved at a dose of 0.3 mg/kg (methadone, 46% ± 1%, P < 0.001 and morphine, 47% ± 1%, P < 0.001 versus placebo, 61% ± 1%, respectively). Naltrindole (5 mg/kg) blocked methadone-induced (0.3 mg/kg) and morphine-induced (0.3 mg/kg) cardioprotection (naltrindole + methadone, 58% ± 1%, P < 0.001 versus methadone; and naltrindole + morphine, 58 ± 1%, P < 0.001 versus morphine). Methadone (0.3 mg/kg) reduced myocardial IS when given 5 min before reperfusion (46% ± 1%, P < 0.001 versus placebo) but not 10 s after reperfusion (60% ± 1%, P = 0.675 versus placebo). No significant myocardial IS differences were seen for placebo when comparing the 45-min ischemia group (64% ± 1%) with the 30-min ischemia group (60% ± 1%, P = 0.069). The longer ischemia time of 45 min abrogated methadone-induced IS reduction (64% ± 2%, P = 0.867 versus 45-min ischemia placebo group) and morphine-induced IS reduction (65% ± 1%, P = 0.836 versus 45-min ischemia placebo group). These findings demonstrate that methadone and morphine produce similar myocardial IS-sparing effects that are δ-opioid receptor mediated and that are dependent on the duration of myocardial ischemia.