Background and Objective: Kyotorphin (KTP), an endogenous analgesic neuropeptide in the central nervous system, is considered to be a neurotransmitter or neuromodulator. D-kyotorphin (D-KTP) is a synthetic analogue of KTP. Both peptides bind to a specific receptor and induced Met-enkephalin release. Thus, the effects of both peptides fall into two clearly identifiable groups: the ones, mediated via opioid peptides and the opioid peptideindependent ones. For a long time we have been interested in the neuromodulating properties of KTP and D-KTP in analgesia due to different types of stress. Our previous data showed that both peptides reduced stress-induced analgesia, which suggest that they may act as an anti-opioid peptides counteracting the effects of stress. During acute stress increased secretion of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) plays a key regulatory role on the basal activity of the hypothalamic-pituitary-adrenal axis and on the termination of the stress response. The aim of this study was to compare changes in ACTH and CORT concentration after various stressors, as well as after injection of KTP or D-KTP. Materials and Methods: The male Wistar rats were injected with KTP or D-KTP immediately after exposure of acute immobilization, cold and heat stresses. After decapitation plasma ACTH and CORT were assayed by a double antibody radioimmunoassay method. Results and Conclusion: The various stressors applied seem to induce a different response of the HPA system as judged by quantitative changes in ACTH and CORT release. In addition, this study points to KTP and its synthesized optical isomer D-KTP as a possible antistressor substances with potential clinical importance in the context of stress-related disorders, since they inhibited stress-induced elevations in two investigated hormones helping the organism to reach homeostatic level. Further studies are needed to understand the exact role of KTP in stress response.