Darmani N A, Saady J J, Schnoll S H, Martin B R
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
Neurotoxicol Teratol. 1991 Nov-Dec;13(6):627-30. doi: 10.1016/0892-0362(91)90046-y.
The effects of a 14-day (gestation days 7-20) chronic methadone (6.3-9.0 mg/kg/day) infusion via osmotic minipumps were studied on the induction of physical dependence in both pregnant and nonpregnant female rats. Following continued methadone exposure, an acute injection of naloxone (2.0 mg/kg, SC) produced the following symptoms of withdrawal in both pregnant and nonpregnant methadone-exposed rats: increased frequency of head shakes, teeth-chattering and face-rubbing episodes, as well as the induction of burrowing, diarrhea, facial tremor, squeaking and vaginal sniffing. Increased fetal movement in the maternal abdomen was also observed in the pregnant rats. In the saline-exposed pregnant controls, naloxone failed to induce a significant effect. In addition, brain and plasma methadone levels during the various stages of pregnancy (gestation days 8-20) were determined. The methadone levels in plasma were initially variable (gestation days 8-12) but became more constant (approximately 50 ng/ml) from gestation day 14 to 20. Methadone brain levels also followed a similar pattern, except that the brain methadone content was at least 20-fold greater than plasma concentrations at any given time. Thus, relative to the high brain levels, the present data suggest that acute changes in methadone plasma concentration may not be a good index of pharmacological effect.
通过渗透微型泵对怀孕和未怀孕的雌性大鼠进行为期14天（妊娠第7 - 20天）的慢性美沙酮（6.3 - 9.0毫克/千克/天）输注，研究其对身体依赖性诱导的影响。在持续接触美沙酮后，对怀孕和未怀孕且接触过美沙酮的大鼠急性注射纳洛酮（2.0毫克/千克，皮下注射）会产生以下戒断症状：摇头、磨牙和擦脸发作的频率增加，以及出现打洞、腹泻、面部震颤、尖叫和阴道嗅探行为。在怀孕大鼠中还观察到母鼠腹部胎儿活动增加。在暴露于生理盐水的怀孕对照组中，纳洛酮未能诱导出显著影响。此外，还测定了怀孕各阶段（妊娠第8 - 20天）大脑和血浆中的美沙酮水平。血浆中美沙酮水平最初变化不定（妊娠第8 - 12天），但从妊娠第14天到20天变得更加稳定（约50纳克/毫升）。美沙酮的脑内水平也呈现类似模式，只是在任何给定时间，脑内美沙酮含量比血浆浓度至少高20倍。因此，相对于高脑内水平，目前的数据表明美沙酮血浆浓度的急性变化可能不是药理作用的良好指标。
