The neurochemical mechanisms underlying the coincident activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system in response to stress remain unclear. Central injection of the neuropeptide bombesin (BN) potently stimulates the release of epinephrine from the adrenal medulla, adrenocorticotropic hormone (ACTH) from the pituitary gland, and elicits behaviors typically associated with increased emotionality and arousal. The current studies assessed whether stress is associated with 1) fluctuations in the endogenous regional levels of BN-like peptides and/or 2) changes in BN receptor density. Male Sprague-Dawley rats received either no treatment or were subjected to acute immobilization stress for 10, 30 or 120 min. Plasma ACTH levels increased in response to stress, peaking at 30 min. BN-like immunoreactivity increased significantly at the hypothalamus and medulla, within 30 min; however with more sustained immobilization (120 min) BN-like immunoreactivity declined to control levels. Levels of BN-like peptides remained unchanged in several other regions, including the hippocampus, striatum, midbrain, pituitary, and pons. Autoradiographic analysis revealed that the density of BN receptor varied in a regionally specific manner. Significant stress related increases in binding were found at the nucleus of the solitary tract (at 30 and 120 min), and at the paraventricular (at 120 min) and arcuate nuclei (at 120 min) of the hypothalamus. These data indicate the BN-like peptides may play a role in the mediation and/or modulation of response to stress.