It has previously been shown that rat adrenal zona medullaris possesses an interleukin-1 beta (IL-1 beta)-responsive peripheral branch of the CRH/ACTH system that duplicates the hypothalamopituitary central one (Mazzocchi et al., Mol. Cell. Neurosci. 4: 267, 1993). The intraadrenal content of corticotropin-releasing hormone (CRH) and adrenocorticotropin (ACTH) immunoreactivities (ir), as well as IL-1 beta-stimulated release of CRH-ir and ACTH-ir, increased in relation to the number of days elapsed from hypophysectomy; the effect of hypophysectomy required at least 48 h to become significant and reached its maximum after 72 h. The action of IL-1 beta on ACTH-ir release was annulled by simultaneous exposure to alpha-helical-CRH, an antagonist of CRH. ACTH infusion, at a rate restoring a normal blood level of the hormone, prevented the effect of hypophysectomy on intraadrenal concentrations of both CRH-ir and ACTH-ir; similarly, the hypophysectomy-evoked rise in intraadrenal ACTH-ir content was completely annulled by treating hypophysectomized rats with CRH or dexamethasone. Taken together our findings suggest that the elimination of the central branch of CRH/ACTH system induces a marked increase in the activity of the intraadrenal peripheral one. The hypothesis is advanced that the hypophysectomy-induced lowering of circulating ACTH and the consequent drop in the production of adrenal glucocorticoids enhances, via a classic negative feedback mechanism, gene expression of CRH and ACTH in adrenal medullary chromaffin cells.