Foss J F, Yuan C S, Roizen M F, Goldberg L I
Committee on Clinical Pharmacology, The University of Chicago, IL 60637, USA.
Cancer Chemother Pharmacol. 1998;42(4):287-91. doi: 10.1007/s002800050819.
Morphine can have either an emetic or an antiemetic effect. The emetic effect of morphine can be blocked by methylnaltrexone (MNTX), a quaternary opioid antagonist with peripheral action. In this study, we tested the hypothesis that administering MNTX to block the peripheral emetic effect of morphine would unmask the central antiemetic effect of the morphine. The net result, we hypothesized, would be a reduction in apomorphine- or cisplatin-induced emesis.
MNTX 0.25 mg/kg and morphine 1 mg/kg were administered to conscious dogs which were then challenged with the potent emetic agents apomorphine or cisplatin. Emesis was assessed by the presence of characteristic retching motions accompanied by the regurgitation of gastric contents.
We observed that apomorphine challenges of 0.1 mg/kg and of 0.03 mg/kg produced 100% emesis in control animals. After pretreatment with MNTX and morphine, the frequency of emesis with the larger dose of apomorphine was reduced to 50% and with the smaller dose to 22%. MNTX alone did not block apomorphine-induced emesis. In animals challenged with cisplatin 3 mg/kg, the emetic response was 100%. Emesis did not occur in animals pretreated with MNTX 0.25 mg/kg and morphine 1 mg/kg before cisplatin.
Our results demonstrate that MNTX combined with morphine reduces apomorphine-induced emesis and blocks cisplatin-induced emesis. These results support the hypothesis that the emetic effect of morphine is peripheral and its antiemetic action is central. In combination, MNTX and morphine may have a clinical role in the treatment of chemotherapy-induced emesis.
吗啡可产生催吐或止吐作用。吗啡的催吐作用可被甲基纳曲酮（MNTX）阻断，MNTX是一种具有外周作用的季铵类阿片拮抗剂。在本研究中，我们检验了这样一个假设，即给予MNTX以阻断吗啡的外周催吐作用会揭示吗啡的中枢止吐作用。我们推测，最终结果将是阿扑吗啡或顺铂诱导的呕吐减少。
给清醒的犬注射0.25mg/kg的MNTX和1mg/kg的吗啡，然后用强效催吐剂阿扑吗啡或顺铂对其进行激发试验。通过观察伴有胃内容物反流的特征性干呕动作来评估呕吐情况。
我们观察到，0.1mg/kg和0.03mg/kg的阿扑吗啡激发试验在对照动物中产生了100%的呕吐率。在用MNTX和吗啡预处理后，较大剂量阿扑吗啡引起的呕吐频率降至50%，较小剂量降至22%。单独使用MNTX并不能阻断阿扑吗啡诱导的呕吐。在用3mg/kg顺铂激发的动物中，催吐反应为100%。在顺铂给药前用0.25mg/kg的MNTX和1mg/kg的吗啡预处理的动物中未发生呕吐。
我们的结果表明，MNTX与吗啡联合使用可减少阿扑吗啡诱导的呕吐，并阻断顺铂诱导的呕吐。这些结果支持了这样的假设，即吗啡的催吐作用是外周性的，其止吐作用是中枢性的。MNTX和吗啡联合使用可能在化疗引起的呕吐治疗中具有临床作用。
