Effects of hexarelin and isolation stress on the Met-enkephalin system in young lambs

Abstract

Koziec K., S canes C.G., Z ubel-Łojek J., Gajewska A. 2023. Effects of hexarelin and isolation stress on the Met-enkephalin system in young lambs. Folia Biologica (Kraków) 71: 195-206.Stress stands out as the primary instigator of numerous diseases – ranging from cardiovascular and gastro- intestinal to diabetes and nervous disturbances – in most developed nations. Endogenous opioid peptides (EOP), particularly Met-enkephalin, play a crucial role in mitigating the up-regulation of the hypothalamo- pituitary-adrenal axis during stress responses, consequently reducing the risk of serious diseases. Hexarelin, a synthetic analog of Met-enkephalin, has been predominantly investigated for its impact on growth hormone (GH) release in both human subjects and rodent models. This study was undertaken to evaluate the influence of isolation stress and/or hexarelin administration on various Met-enkephalin-related parameters in a novel animal model – 3-month-old lambs. Four distinct groups were established: a control group, a group intravenously injected with hexarelin, a group subjected to 60 min of isolation stress from the herd, and a group treated with both hexarelin and stress. Blood and hypothalamus samples were collected to analyze cortisol and Met-enkephalin profiles, proenkephalin (PENK) gene expression, Met-enkephalin concentration, in vitro Met-enkephalin secretion, and opioid receptor binding. The findings revealed a significant impact of stress on all assessed parameters. Hexarelin alone led to a decrease in cortisol levels and Met-enkephalin synthesis, release, and receptor binding in the hypothalamus. When administered prior to stress, hexarelin potentiated the responses of opioid parameters to isolation. These results, for the first time, demonstrate that hexarelin interacts with Met-enkephalin, modulating the stress response at both central and peripheral levels in growing lambs. It is suggested that hexarelin plays a crucial role during stress responses; however, further research on its effects should be conducted concurrently with the examination of opioid profiles.