Umans J G, Inturrisi C E
Eur J Pharmacol. 1982 Dec 3;85(3-4):317-23. doi: 10.1016/0014-2999(82)90218-7.
The acute toxicity of heroin (3,6-diacetylmorphine, DAM) and its metabolites 6-acetylmorphine (AM) and morphine (M) following intravenous (i.v.) and intracerebroventricular (i.c.v.) administration and their tailflick-test analgesic activity following i.c.v. administration were studied in mice. After i.c.v. administration, M was 2.5-3 times more potent as a naloxone-reversible analgesic than either DAM or AM. DAM and AM provoked a naloxone-sensitive respiratory depressant lethality (i.c.v.) while M (i.c.v.), and all three drugs given i.v., caused convulsions prior to death. The dose-response and naloxone antagonism studies suggest that the receptor mechanisms which may subserve opiate convulsions differ from those mediating either analgesia or depressant lethality. Studies of DAM's disposition in vivo and in vitro suggest that unhydrolyzed DAM may contribute to its own pharmacodynamic profile after i.v., but not subcutaneous (s.c.) administration to mice.
在小鼠中研究了海洛因（3,6 - 二乙酰吗啡，DAM）及其代谢产物6 - 乙酰吗啡（AM）和吗啡（M）静脉注射（i.v.）和脑室内注射（i.c.v.）后的急性毒性，以及i.c.v.给药后的甩尾试验镇痛活性。i.c.v.给药后，作为纳洛酮可逆性镇痛药，M的效力比DAM或AM高2.5至3倍。DAM和AM引发了纳洛酮敏感的呼吸抑制致死性（i.c.v.），而M（i.c.v.）以及静脉注射的所有三种药物在死亡前均引起惊厥。剂量反应和纳洛酮拮抗研究表明，可能导致阿片类惊厥的受体机制不同于介导镇痛或抑制致死性的机制。DAM在体内和体外处置的研究表明，未水解的DAM在静脉注射后可能对其自身的药效学特征有贡献，但对小鼠皮下（s.c.）给药则不然。
