Early life events have been implicated in the programming of adult chronic diseases. Several investigations suggest that the role of early environment in influencing development mainly involves the hypothalamic-pituitary-adrenal axis. Therefore, we examined whether 1) daily neonatal handling, applied from birth to weaning induces HPA hormones alterations in mice lasting up to the adult age; and 2) if the administration of an antisense oligodeoxynucleotide versus pro-opiomelanocortin (As-POMC) prevents hormonal alterations observed in previously handled mice (Handled). In the adult phase (90 days), Handled are overweight and have higher basal plasma immuno-reactive (ir)-corticosterone and adrenocorticotropin (ir-ACTH), and higher pituitary ir-ACTH; while they have lower hypothalamic ir-ACTH and corticotropin-releasing hormone (ir-CRH) in comparison with the non-handled mice. As-POMC (0.05-0.1 nmol/g body weight per day) administered during the same period dose-dependently prevents the increase in body weight, in plasma ir-corticosterone, ir-ACTH, and pituitary ir-ACTH, also preventing the decrease in hypothalamic ir-CRH and ir-ACTH; while the mismatch oligonucleotide is nearly inactive. This data indicates that pharmacological treatment in neonatal life may have enduring effects, reducing the alterations in hormonal homeostatic programming mechanisms induced by early repeated handling.