摘要
背景美沙酮是一种阿片激动剂，常用于治疗急慢性疼痛。本文探讨美沙酮是否与吗啡一样剂量依赖地减少心肌梗死面积（infarctsize，IS）及其机制是否由δ-阿片受体介导。此外还检测心肌IS的减少是否随美沙酮给药时间或诱发缺血持续时间而发生变化。方法做好手术准备后，将雄性SD大鼠分为3组。第1组又分为缺血前30分钟接受美沙酮（0．03-3mg／kg）、吗啡（0．03-3mg／kg）和水（安慰剂）的3个亚组。第1组的部分动物在给予美沙酮（0．3mg／kg）、吗啡（0．3mg／kg）或安慰剂前也注射8．阿片拮抗剂纳曲吲哚（5mg／kg）。第2组分为再灌注前5分钟或再灌注后10秒接受美沙酮（0．3mg／kg）治疗亚组。这2组中的动物通过左前降支冠状动脉夹闭造成心肌缺血30分钟，然后再灌注2小时。第3组动物通过夹闭左前降支冠状动脉造成缺血45分钟，于再灌注前5分钟接受安慰剂，美沙酮（0．3mg／kg），或吗啡（0．3mg／kg），然后再灌注2小时。用三苯基氯化四唑染色心肌组织评价心肌IS，以危险区（areaatrisk，AAR）所占百分比表示（均数±标准误）。结果缺血前给予美沙酮或吗啡可减少心肌IS。最大效应出现于0．3mg／kg剂量组（美沙酮，46％±1％，P〈0．001和吗啡，47％±1％，P〈0．001，与安慰剂的61％±1％相比）。纳曲吲哚（5mg／kg）阻断美沙酮（0．3mg／kg）和吗啡（0．3mg／kg）诱导的心肌保护作用（与美沙酮相比，纳曲吲哚＋美沙酮，58％±1％，P〈0．001，与吗啡相比，纳曲吲哚＋吗啡，58％±1％，P〈0．001）。再灌注前5分钟给予美沙酮（0．3mg／kg）时减少心肌IS（与安慰剂相比，46％±1％，P〈0．001，），但再灌注后10秒时给予美沙酮则无这种效应（与安慰剂相比，60％±1％，P=0．675）。安慰剂组与45分钟缺血组（64％±1％）和30分钟缺血组（60％±1％，尸=0．069）比较，末见心肌IS明显差别。45分钟较长缺血时间抵消了美沙酮（与45分钟缺血安慰剂组比较，64％±2％，P=0．867，）和吗啡（与45分钟缺血安慰剂组比较，65％±1％，P=0．836）诱导的IS减少。结论这些结果证明美沙酮和吗啡产生类似的保护心肌IS效应，这种效应由8．阿片受体所介导，依赖于心肌缺血持续时间。
BACKGROUND： 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. METHODS： 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 ocdusion 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 rain 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 ± sere）. RESULTS： 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 versusmethadone; and naltrindole morphine, 58 ±1%, P 〈 0. 001 versus morphine）. Methadone （0.3 mg/kg） reduced myocardial lS 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-rain ischemia group （64% ±1%） with the 30-min ischemia group （60% ±1%, P = 0. 069）. The longer ischemia time of 45 rain 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）. CONCLUSIONS： 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.
出处
《麻醉与镇痛》
2013年第1期1-8,共8页
Anesthesia & Analgesia
