Early neonatal experience of Long-Evans rats results in long-lasting changes in morphine tolerance and dependence
Early neonatal experience of Long-Evans rats results in long-lasting changes in morphine tolerance and dependence
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DOI：
10.1007/s002130100806
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发表时间：
2001-09-01
影响因子：
3.4
通讯作者：
Holtzman, SG
中科院分区：
文献类型：
--
作者：
Kalinichev, M;Easterling, KW;Holtzman, SG
理论基础：在Long-Evans大鼠出生后2-14天，每天3小时的隔离会导致行为和神经内分泌对应激源的反应以及对急性吗啡的敏感性发生长期变化。目的：我们测试了在出生后第2-14天每天脱离母体3小时(MS)的子代是否表现出对慢性吗啡的敏感性改变，与同期仅经历短暂(15分钟)脱离母体(H)或保持不受干扰(NH)的动物相比。方法：受试者接受1周的SC输注吗啡或生理盐水通过渗透压泵。在泵移除20小时后，记录全球阿片类药物戒断评分。四小时后，动物在累积注射吗啡的过程中接受抗伤害感觉测试(甩尾和热板测试)。结果：与NH对照组相比，接受慢性吗啡戒断的MS男性和MS女性的整体戒断评分更高。与H和NH对照组相比，MS男性(但不是MS女性)对吗啡的抗伤害感受作用不那么敏感，主要是在热板试验中，无论他们是接受了生理盐水还是吗啡输注。MS男性持续表现出显著的吗啡耐受性，而对照组男性在热板试验(NH组)或两种抗伤害试验(H组)中都没有表现出耐受性。相比之下，所有女性在两项抗伤害感受测试中都表现出了耐受性。结论：这些数据表明，反复的新生儿母体分离以性别依赖的方式改变了对慢性吗啡给药的敏感性。
Rationale: Daily, 3-h separations from the dam on postnatal days 2-14 produce long-lasting changes in behavioral and neuroendocrine responses to stressors and sensitivity to acute morphine in Long-Evans rats. Objective: We tested whether offspring that were separated from their dam for 3 h daily (MS) on postnatal days 2-14 exhibit altered sensitivity to chronic morphine, compared to animals that experienced only brief (15 min) separations (H) from the dam or that were left undisturbed (NH) during the same period. Methods: Subjects received I week SC infusion of either morphine, or saline via osmotic pumps. Twenty-hours after pump removal, the global opioid withdrawal scores were recorded. Four hours later, animals were tested for antinociception (tail-flick and hot-plate tests) during cumulative morphine administration. Results: MS males and MS females undergoing withdrawal from chronic morphine had higher global withdrawal scores compared to NH controls. MS males (but not MS females) were less sensitive to the antinociceptive effects of morphine compared to H and NH controls, primarily in the hot-plate test, regardless of whether they had received a saline or a morphine infusion. MS males consistently exhibited significant morphine tolerance, whereas control males failed to exhibit tolerance either in the hot-plate test (NH group) or in both antinociception assays (H group). In contrast, tolerance was exhibited by all females in both tests for antinociception. Conclusions: These data indicate that repeated neonatal maternal separation alters sensitivity to chronic morphine administration in a sex-dependent manner.