Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system
Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system
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DOI：
10.1038/sj.npp.1300872
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发表时间：
2006-06-01
影响因子：
7.6
通讯作者：
Chavkin, Charles
中科院分区：
文献类型：
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作者：
McLaughlin, Jay P.;Li, Shuang;Chavkin, Charles
先前的研究表明，重复强迫游泳应激诱导的行为（包括镇痛，不动，增加药物奖励）是由内源性强啡肽原衍生的阿片肽的释放和随后的κ阿片受体（KOR）的激活介导的。我们用一种不同类型的压力情境来测试这些效应的普遍性：反复的社交失败。C57 B1/6小鼠在社交失败应激（SDS）中表现出特征性的应激诱导的不动和失败的姿势反应，以及应激诱导的镇痛（SIA）。每天用KOR拮抗剂nor-binaltorphimine（nor-BNI，10 mg/kg，i. p.）阻断SIA，并显着减少应激诱导的不动性SDS暴露的第二和第三天。相比之下，前强啡肽基因被破坏的小鼠在反复暴露于SDS后，不动性、社交失败姿势或SIA没有显著增加。由于压力和κ阿片系统可以调节对滥用药物的反应，我们测试了SDS对可卡因条件性位置偏爱（CPP）的影响。用可卡因（15 mg/kg，s.c.）显示出药物配对室的位置偏好比未应激小鼠的反应显著增强。Nor-BNI预处理阻断可卡因CPP的应激诱导的增强作用。与这一结果一致，缺乏前强啡肽基因的小鼠没有表现出可卡因CPP的应激诱导增强，而野生型同窝出生的小鼠则表现出这种增强。研究结果表明，慢性SDS可能会激活κ阿片系统产生镇痛，不动，社会失败的姿势，并导致可卡因的急性奖励性质的增强。
Previous studies have demonstrated that repeated forced-swim stress-induced behaviors (including analgesia, immobility, and increased drug reward) were mediated by the release of endogenous prodynorphin-derived opioid peptides and subsequent activation of the kappa opioid receptor (KOR). We tested the generality of these effects using a different type of stressful situation: repeated social defeat. C57Bl/6 mice subjected to social defeat stress (SDS) over 3 days showed a characteristic stress-induced immobility and defeated-postural response, as well as stress-induced analgesia (SIA). Daily pretreatment with the KOR antagonist nor-binaltorphimine (nor-BNI, 10 mg/kg, i.p.) blocked the SIA and significantly reduced the stress-induced immobility on the second and third days of SDS exposure. In contrast, prodynorphin gene-disrupted mice showed no significant increase in immobility, socially defeated postures, or SIA following repeated exposure to SDS. Since both stress and the kappa opioid system can modulate the response to drugs of abuse, we tested the effects of SDS on cocaine-conditioned place preference (CPP). SDS-exposed mice conditioned with cocaine (15 mg/kg, s.c.) showed significant potentiation of place-preference for the drug-paired chamber over the responses of unstressed mice. Nor-BNI pretreatment blocked stress-induced potentiation of cocaine-CPP. Consistent with this result, mice lacking the prodynorphin gene did not show stress-induced potentiation of cocaine-CPP, whereas wild-type littermates did. The findings suggest that chronic SDS may activate the kappa opioid system to produce analgesia, immobility, social defeat postures, and resulting in a potentiation of the acute rewarding properties of cocaine.