The review focuses on the role of hypothalamic-pituitary-adrenocortical system (HPAS) in regulation of pain sensitivity and discusses the mechanisms involved in this process. Analgesic effects of exogenous hormones of HPAS (corticotropin-releasing hormone (CRH), ACTH, glucocorticoids) have been shown in rats. It is mediated by both opioid and non-opioid mechanisms. Endogenous glucocorticoids produce development of analgesia mediated by non-opioid mechanisms. Analgesic effect of ACTH is mediated by both non-glucocorticoids mechanisms associated with endogenous glucocorticoids and opioid mechanisms. In contrast to ACTH, analgesic effect of CRH is mediated only by non-opioid mechanisms associated or dissociated with endogenous glucocorticoids. The neurons of midbrain periaqueductal gray matter may be involved in the analgesia induced by glucocorticoids.