As a neurotransmitter or neuromodulator, brain histamine has a variety of physiological roles in brain functions such as hypothalamic- pituitary- adrenal (HPA) activity. Histamine induces the release of ACTH through the activation of hypothalamic neurons containing vasopressin and CRH. Histamine induces the activity of HPA axis directly or indirectly. Endogenous opioids modulate the (HPA) axis activity as well. In order to consider the interaction between morphine and pyrilamine in HPA axis, the adult male Wistar rats were administered morphine (0.5, 1, 1.5, 3 mg/kg), and pyrilamine (1, 5, 10, 20 mg/kg) respectively. Thirty minutes after injection, the rats were anesthetized and blood samples were collected for hormonal investigations. The result showed that morphine dose-dependently and also pyrilamine decreased the cortisol concentration in the serum. The treatment of morphine and pyrilamine together decreased cortisol level significantly and there is a close correlation between pyrilamine and morphine in cortisol secretion.