When arousal behavior underlies stress hormone secretion and increased autonomic function: Lessons learned from the study of Neuropeptide W

Neuropeptide W (NPW) has been identified as the endogenous ligand for G protein-coupled receptors NPBWR1 (GPR7) and NPBWR2 (GPR8). NPW immunoreactivity is present in limbic system and reticular activating system areas known to be important in arousal, as well as hypothalamic nuclei known to be important in food and water intake and the neuroendocrine response to stress. In rat, central administration of NPW increased mean arterial pressure (MAP) and behaviors associated with locomotion and grooming. I hypothesized that the NPW-induced increase in MAP is secondary to an increase in locomotion and grooming. Since peptides that stimulate arousal have been shown to increase sympathetic activity (e.g. orexin), I tested the ability of the mixed alpha 1- and alpha 2-adrenergic antagonist, phentolamine, to block the NPW-23-induced rise in MAP. Phentolamine pretreatment abrogated the NPW-induced MAP increase. However, animals no longer exhibited behavioral arousal when pretreated with phentolamine prior to NPW administration. Anesthesia also blocked the NPW-induced increase in MAP. These results suggest that NPW increased MAP secondary to increased behavioral arousal. Experiments were designed to evaluate the physiological relevance of NPW in food and water intake and the neuroendocrine response to stress. Compromise of endogenous NPW production by siRNA administration abrogated the water intake and cardiovascular effects of angiotensin II, and prolactin secretion, but failed to alter corticosterone, secretion in response to restraint stress. These results suggest that endogenous NPW may be a physiologically relevant, downstream mediator of the central actions of angiotensin II to stimulate thirst and increase arterial pressure. In addition, NPW-producing neurons appear to participate in the hypothalamic mechanisms controlling prolactin secretion.;Elucidation of the hierarchy of neuronal circuits activated during stress may provide insight into how the brain controls and integrates the appropriate responses to stress, including autonomic, endocrine, and behavioral responses. With that knowledge the pathogenesis of diseases that can develop under chronic stressful conditions, such as obesity and hypertension, may be better understood, facilitating the development of novel therapeutic strategies to prevent or alleviate the impact of these conditions.