Opp M R, Imeri L
Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston, Tex., USA.
Neuroendocrinology. 2001 Apr;73(4):272-84. doi: 10.1159/000054644.
Corticotropin-releasing hormone (CRH) is a mediator of responses to a variety of stressors, including immune challenge. CRH and the hypothalamic-pituitary-adrenal (HPA) axis constitute a negative feedback mechanism for actions of immunomodulators, such as interleukin (IL) 1. CRH is a potent inducer of waking, whereas IL-1 induces slow-wave sleep (SWS). We hypothesize that the complex changes in sleep-wake behavior during immune challenge are mediated in part by CRH and its antagonism of IL-1-induced enhancement of SWS. To further explore this hypothesis, we administered IL-1beta intracerebroventricularly into rats of genetically related strains that differ in CRH/HPA axis responsiveness to IL-1 and determined subsequent alterations in their sleep-wake behavior. Sprague-Dawley rats responded to central administration of IL-1 with alterations in sleep-wake behavior as previously reported; SWS increased, and rapid eye movement sleep (REMS) and waking decreased. CRH and the HPA axis of Lewis rats are reported to be hyporesponsive to challenge; the onset of the IL-1-induced increase in SWS was quicker and the peak magnitude of the response greater than in Sprague-Dawley rats. In contrast, Fischer 344 rats exhibit greater CRH release and HPA axis activation in response to IL-1. IL-1 induced a profound and transient increase in waking of Fischer 344 rats before SWS increased. The febrile responses to IL-1 of Fischer 344 and Lewis rats were identical and of greater magnitude than those observed in Sprague-Dawley rats. Pretreatment with the CRH receptor antagonist alpha-helical CRH(9-41) blocked the initial IL-1-induced increase in waking of Fischer 344 rats. CRH receptor blockade did not affect the IL-1-induced alterations in sleep-wake behavior of Lewis or Sprague-Dawley rats or brain temperature of any rat strain. These observations support the hypothesis that CRH is both a modulator of responses to IL-1 and is involved in the regulation of waking.
促肾上腺皮质激素释放激素（CRH）是机体对包括免疫应激在内的多种应激源作出反应的一种介质。CRH与下丘脑 - 垂体 - 肾上腺（HPA）轴构成了针对免疫调节剂（如白细胞介素（IL）1）作用的负反馈机制。CRH是觉醒的强效诱导剂，而IL - 1诱导慢波睡眠（SWS）。我们推测，免疫应激期间睡眠 - 觉醒行为的复杂变化部分是由CRH及其对IL - 1诱导的SWS增强的拮抗作用介导的。为了进一步探究这一假说，我们将IL - 1β脑室内注射到对IL - 1的CRH/HPA轴反应性不同的遗传相关品系大鼠中，并确定其随后睡眠 - 觉醒行为的变化。如先前报道，Sprague - Dawley大鼠对脑室内注射IL - 1的反应是睡眠 - 觉醒行为发生改变；SWS增加，快速眼动睡眠（REMS）和觉醒减少。据报道，Lewis大鼠的CRH和HPA轴对刺激反应低下；与Sprague - Dawley大鼠相比，IL - 1诱导的SWS增加的起始更快，反应的峰值幅度更大。相比之下，Fischer 344大鼠对IL - 1表现出更大的CRH释放和HPA轴激活。在SWS增加之前，IL - 1诱导Fischer 344大鼠的觉醒出现深刻而短暂的增加。Fischer 344大鼠和Lewis大鼠对IL - 1的发热反应相同，且比Sprague - Dawley大鼠中观察到的反应幅度更大。用CRH受体拮抗剂α - 螺旋CRH(9 - 41)预处理可阻断IL - 1最初诱导的Fischer 344大鼠觉醒增加。CRH受体阻断不影响IL - 1诱导的Lewis或Sprague - Dawley大鼠睡眠 - 觉醒行为的改变，也不影响任何大鼠品系大脑温度。这些观察结果支持了这样的假说，即CRH既是对IL - 1反应的调节因子，又参与觉醒的调节。
