Hypocretin/Orexin acts pharmacologically in hypothalamus to stimulate stress hormone secretion at least in part by an action in the hypothalamic paraventricular nucleus where orexin receptors have been localized. In addition orexin acts in brain to increase sympathetic tone and therefore mean arterial pressure and heart rate. We provide evidence for the role of endogenously produced hypocretin/orexin in the physiologic response to immobilization stress and identify the receptor subtype responsible for this action of the peptide. Antagonism of the type-1 receptor in brain prevented the ACTH-stimulating effect of centrally administered hypocretin/orexin. Furthermore, pretreatment of animals with the hypocretin/orexin type-1 receptor antagonist blocked the ACTH response to immobilization/restraint stress. The type-1 receptor antagonist did not, however, block the pharmacologic or physiologic releases of prolactin in these two models. Antagonism of the type-1 receptor also blocked the central action of orexin to elevate mean arterial pressures and heart rates in conscious rats. These data suggest receptor sub-type selective responses to hypocretin/orexin and provide further evidence for the importance of endogenously produced peptide in the physiologic control of stress hormone secretion.