In the present study, the regulation of tumor necrosis factor-alpha (TNF-alpha) production by alpha(2)- and beta-adrenoceptors located on noradrenergic nerve terminals and on macrophages was studied in endotoxaemic mice. We found that reduction of the sympathetic outflow by reserpine dramatically increased the lipopolysaccharide (LPS)-induced TNF-alpha production, demonstrating that the release of endogenous noradrenaline (NA), controlled by presynaptic alpha(2)-adrenoceptors, was a determinant factor in this model. By using alpha(2)- and beta-adrenergic drugs (clonidine, CH-38083, isoproterenol, propranolol) we provided the first in vivo evidence that, beside the dominance of neuronal alpha(2)- and macrophage beta-adrenoceptors, the alpha(2)-adrenoceptors on macrophages were also involved in the modulation of LPS-induced TNF-alpha production. Since adrenergic drugs are widely used in the clinical practice, our findings may have therapeutical implications. (C) 2000 Published by Elsevier Science B.V. All rights reserved.