Murphey L J, Olsen G D
Department of Pharmacology, School of Medicine, Oregon Health Sciences University, Portland.
J Pharmacol Exp Ther. 1994 Jan;268(1):110-6.
Morphine-6-beta-D-glucuronide (M6G) is a metabolite of morphine with opioid activity in adults. No data are available, however, on the developmental pharmacology of M6G including investigation of the respiratory effects of M6G in the neonate. A randomized, placebo-controlled study comparing the time-action, dose-response and potency of the respiratory effects of M6G to morphine was done using a nonanesthetized neonatal guinea pig model and a noninvasive computerized plethysmograph technique. Respiration was measured while the neonate breathed room air followed by 5% CO2 in air. M6G (0.5-5.0 mg/kg) and morphine (1.5-15 mg/kg) administered subcutaneously decreased ventilation in 3-, 7- and 14-day-old neonatal guinea pigs given a 5% CO2 challenge. During CO2 inhalation, time-to-peak action for M6G occurred 21 min later than for morphine. At maximal ventilatory depression on day 3, a dose of 1.5 mg/kg morphine or M6G decreased minute ventilation while breathing 5% CO2 by 30% compared to placebo. Ventilation also decreased as a function of age in both placebo and drug-treated animals. The percent respiratory depression relative to placebo remained constant for a given dose of morphine as the neonate aged, but not for M6G, which increased in potency. M6G was equipotent to morphine on day 3 after birth, but was 8-fold more potent by day 7. This increase in potency persisted through day 14. The increased potency of M6G that accompanies aging may be caused by either a change in M6G disposition or a change in opioid receptors during development of the neonatal guinea pig.
吗啡-6-β-D-葡萄糖醛酸苷（M6G）是吗啡的一种代谢产物，在成年人中具有阿片样活性。然而，目前尚无关于M6G发育药理学的数据，包括对新生儿M6G呼吸作用的研究。本研究采用非麻醉新生豚鼠模型和无创计算机化体积描记技术，进行了一项随机、安慰剂对照研究，比较M6G与吗啡呼吸作用的时效关系、剂量反应和效能。在新生豚鼠呼吸室内空气后，再呼吸含5%二氧化碳的空气时测量呼吸。皮下注射M6G（0.5 - 5.0mg/kg）和吗啡（1.5 - 15mg/kg）可降低3日龄、7日龄和14日龄接受5%二氧化碳刺激的新生豚鼠的通气量。在吸入二氧化碳期间，M6G达到峰值作用的时间比吗啡晚21分钟。在第3天最大通气抑制时，1.5mg/kg的吗啡或M6G剂量与安慰剂相比，在呼吸5%二氧化碳时可使分钟通气量降低30%。在安慰剂组和药物治疗组动物中，通气量也随年龄增长而降低。对于给定剂量的吗啡，相对于安慰剂的呼吸抑制百分比在新生豚鼠年龄增长过程中保持恒定，但对于M6G则不然，其效能增加。出生后第3天，M6G与吗啡效能相当，但到第7天，其效能提高了8倍。这种效能增加在第14天一直持续存在。M6G效能随年龄增长而增加可能是由于新生豚鼠发育过程中M6G处置的变化或阿片受体的变化所致。
