CRF (also known as corticotropin-releasing hormone) was characterized by Vale et al. in 1981 as a novel 41-amino acid hypothalamic-releasing peptide that stimulates the synthesis and release of adrenocorticotropy hormone (ACTH) and P-endorphin from the pituitary (71). With the early recognition that various internal or external cues disrupting homeostasis result in the release of ACTH and glucocorticoids into the circulation, the stimulation of the hypothalamic-pituitary-adrenal (HPA) axis became one of the major neuroendocrine hallmarks of the adaptive response to stress (3). Now, CRF is well established as the prime hypothalamic hormone involved in the stimulation of the HPA axis during stress (71,72). The population of CRF-synthesizing neurons is predominantly expressed in the parvocellular part of the PVN and projects via the external zone of the median eminence to the anterior pituitary (73). During stress, CRF is delivered into the hypophyseal portal blood vessels and stimulates ACTH release from the pituitary corticotropes. Once into the circulation, ACTH increases the secretion of glucocorticoid hormones from the adrenal cortex (73).
Aside from its role as a hypothalamic hypophysiotropic hormone, CRF acts as a neuro-transmitter in several brain areas (74). In particular, CRF directly administered into the brain reproduces the overall endocrine, behavioral, autonomic, and visceral changes induced by stress in experimental animals, including monkeys (14,24,75,76). Consistent with these observations, immunohistochemical localization of brain CRF established that the peptide is largely distributed throughout the neocortex (prefrontal and cingulate), which mediates behavioral and cognitive components of stress (77). The central nucleus of the amygdala, which is involved in processing the emotional cues, also contains a high density of CRF neurons (78). These neurons project to the LC and increase their firing rate resulting in the stimulation of the ascending noradrenergic system (79). CRF is also located in the subdivision of the hypothalamic (PVN dorsal cap) and pontine nucleus (Barrington's nucleus/LC) that receive stimulatory input from the colon as well as sends direct projections to the intermediolateral column involved in the regulation of autonomic (preganglionic sympathetic and sacral parasympathetic) outflow to the colon (21,80). Consequently, CRF in the PVN and Barrington's nucleus/LC is well positioned to participate in the reciprocal brain-gut interactions, as it pertains to sensory information from the colon and reflex behavioral and autonomic responses of the viscera.
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