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.
Copyright 2001 S. Karger AG, Basel