![]() ![]() Hcrt/ORX-immunopositive fiber staining also has been reported in the median eminence, in particular in the external layer adjacent to the fenestrated capillary endothelium of the hypothalamohypophysial portal vessels ( 6). This would explain the ability of intracerebroventricular injection of a single dose of ORX-A to result in elevated levels of ACTH in plasma ( 14) and multiple doses of orexin to elevate plasma corticosterone concentrations in two additional studies ( 9, 11). In particular, the identification of Hcrt/ORX receptors in the medial parvocellular portion of the paraventricular nucleus suggested an action of the peptides on corticotropin-releasing hormone (CRH) neurons that project to the median eminence. The existence of Hcrt/ORX-immunopositive nerve terminals in neuroendocrine centers in the hypothalamus ( 6-8, 10, 20, 22, 26, 37) and the presence there of mRNA encoding both subtypes of the Hcrt/ORX receptors ( 17, 35) suggested a hypothalamic site of action of the peptides to alter the release of anterior pituitary hormones. Central actions to alter the neuroendocrine regulation of luteinizing hormone (LH) also have been reported ( 23, 35).Īlthough production of the peptides is restricted to a discrete population of neurons in the lateral hypothalamus, the projection fields of these neurons have been identified in numerous brain sites, including the nucleus tractus solitarius, locus ceruleus, ventrolateral medulla, raphe, thalamus, septum, and paraventricular and arcuate nuclei of the hypothalamus ( 7, 20, 22). For example, Hcrt/ORX stimulates arousal ( 9), activates autonomic outflow from the brain ( 5, 27, 32), and acts in the brain to inhibit prolactin (PRL) ( 9, 25) and growth hormone (GH) secretion ( 9) while stimulating ACTH/corticosterone release ( 9, 11, 14). Recent reviews of the literature ( 12, 30) on the Hcrts/ORXs have summarized the findings of numerous groups revealing multiple actions of the peptides, some not directly related to food intake. ( 26) chose the name orexin because of the ability of the peptides to stimulate feeding. The name hypocretin (Hcrt) was chosen because of the peptides' hypothalamic localization and their structural similarity to secretin. ORX-B was first identified as hypocretin-2 (Hcrt2), and ORX-A is the actual structure of the peptide predicted to be hypocretin-1 (Hcrt1) by De Lecea and colleagues ( 8). Posttranslational processing of the orexin gene product results in the formation of two biologically active peptides ( 26): the 33-amino acid ORX-A and the 28-amino acid homolog ORX-B. Our data suggest a direct, pituitary action of the Hcrts/ORXs to modulate the endocrine response to stress and identify the potential cellular mechanism of a unique biological action of the peptides in the anterior pituitary gland. Orexin A and orexin B did not significantly alter basal ACTH secretion in vitro and did not alter basal or releasing factor-stimulated secretion of luteinizing hormone, prolactin, thyroid-stimulating hormone or growth hormone from cells harvested from male or random-cycle female donors. Instead, a G q-mediated signaling mechanism was indicated by the ability of protein kinase C blockade with calphostin C to reverse the inhibitory action of orexin A. The effect was not due to abrogation of the cAMP response of the corticotroph to corticotropin-releasing hormone and was not pertussis toxin sensitive, suggesting a non-G i-mediated mechanism. In vitro studies revealed a dose-related inhibitory effect of the Hcrts/ORXs on corticotropin-releasing hormone-stimulated ACTH secretion that appeared to be mediated via the orexin-1 receptor and to be expressed at doses (threshold dose 1 nM orexin A) similar to the affinity constant for the receptor. We examined the possibility that the Hcrts/ORXs, which we have demonstrated previously to act in the brain to stimulate sympathetic function, could alter stress hormone secretion by a direct pituitary action. Hcrt/ORX receptors are present in the hypothalamus and anterior pituitary gland. ![]() The hypocretin/orexins (Hcrts/ORXs) are peptides produced in neurons in the lateral hypothalamic area that project to neuroendocrine centers in the hypothalamus. ![]()
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