Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, MRC 217, 115 Mill Street, Belmont, MA 02478, USA.
Brain Res. 2010 Feb 16;1314:56-73. doi: 10.1016/j.brainres.2009.09.074. Epub 2009 Sep 24.
Stress is most often associated with aversive states. It rapidly induces the release of hormones and neuropeptides including dynorphin, which activates kappa opioid receptors (KORs) in the central and peripheral nervous systems. In animal models, many aversive effects of stress are mimicked or exacerbated by stimulation of KORs in limbic brain regions. Although KOR signaling during acute stress may increase physical ability (by producing analgesia) and motivation to escape a threat (by producing aversion), prolonged KOR signaling in response to chronic or uncontrollable stress can lead to persistent expression of behavioral signs that are characteristic of human depressive disorders (i.e., "prodepressive-like" signs). Accumulating evidence suggests that KORs contribute to the progressive amplification (sensitization) of stress-induced behaviors that occurs with repeated exposure to stress. Many of the aversive effects of stress are blocked by KOR antagonists, suggesting that these agents may have potential as therapeutics for stress-related conditions such as depression and anxiety disorders. This review summarizes current data on how KOR systems contribute to the acute (rapid), delayed, and cumulative molecular and behavioral effects of stress. We focus on behavioral paradigms that provide insight on interactions between stress and KOR function within each of these temporal categories. Using a simplified model, we consider the time course and mechanism of KOR-mediated effects in stress and suggest future directions that may be useful in determining whether KOR antagonists exert their therapeutic effects by preventing the development of stress-induced behaviors, the expression of stress-induced behaviors, or both.
压力通常与厌恶状态有关。它会迅速释放激素和神经肽，包括强啡肽，后者激活中枢和外周神经系统中的κ阿片受体（KOR）。在动物模型中，应激的许多厌恶效应通过刺激边缘脑区域的 KOR 来模拟或加剧。尽管急性应激期间的 KOR 信号可能会增加身体能力（通过产生镇痛作用）和逃避威胁的动机（通过产生厌恶作用），但对慢性或不可控应激的延长 KOR 信号会导致持久表达与人类抑郁障碍特征一致的行为迹象（即“类抑郁样”迹象）。越来越多的证据表明，KOR 有助于在反复暴露于应激时发生的应激诱导行为的渐进放大（敏化）。许多应激的厌恶效应被 KOR 拮抗剂阻断，这表明这些药物可能具有治疗与应激相关的疾病（如抑郁症和焦虑症）的潜力。这篇综述总结了目前关于 KOR 系统如何导致应激的急性（快速）、延迟和累积分子和行为效应的资料。我们专注于提供有关应激和 KOR 功能之间相互作用的见解的行为范例，这些范例适用于每个时间类别。使用简化的模型，我们考虑了 KOR 介导的应激效应的时间过程和机制，并提出了未来的方向，这可能有助于确定 KOR 拮抗剂是否通过预防应激诱导行为的发展、应激诱导行为的表达或两者兼而有之来发挥其治疗作用。
