The endogenous, peptide ligand for the orphan receptors GPR7 and GPR8 was identified to be neuropeptide W (NPW). Since these receptors are expressed in brain and in particular in hypothalamus, we hypothesized that NPW might interact with neuroendocrine systems that control hormone release from the anterior pituitary gland. No significant effects of NPW were observed on the in vitro releases of PRL, ACTH or GH when log molar concentrations ranging from 1 pM to 100 nM NPW were incubated with dispersed anterior pituitary cells. However, NPW, when injected into the lateral cerebroventricle of conscious, unrestrained male rats, in a dose related fashion elevated PRL and corticosterone and lowered GH levels in circulation. The threshold dose for all three effects was 1.0 nanomole. We conclude that endogenous NPW may play a regulatory role in the organization of neuroendocrine signals accessing the anterior pituitary gland, but does not itself act as a true releasing or inhibiting factor in the gland. Central administration of NPW23 also stimulated water drinking and food intake. The ability of exogenous peptide to decrease GH but stimulate PRL secretion and activate the hypothalamo-pituitary adrenal axis, together with the observed behavioral effects, suggests that endogenous NPW may play a role in the hypothalamic response to stress.