The aim of the present study is to investigate the mechanisms of suppression of splenic natural killer (NK) cytotoxicity caused by cold stress, using 6-hydroxydopamine (6-OHDA) as chemical sympathectomy. The NK activity was measured by (51)chromium release assay. Central sympathectomy with intracerebroventricular (i.c.v.) injection of 6-OHDA reduced significantly the elevation of plasma corticosterone level, the expression of Fos in hypothalamic paraventricular nucleus and in locus coeruleus, as well as the suppression of NK activity induced by cold stress at 4 degrees C for 4 h. Peripheral sympathectomy with intraperitoneal (i.p.) injection of 6-OHDA and blockade of beta-adrenergic receptor with i.p. injection of propranolol also reversed the cold stress-induced suppression of NK cytotoxicity, but without significant effect on Fos expression in brain. The results suggest that the activation of hypothalamic-pituitary-adrenal axis induced by cold stress might be mediated, at least partially, by central noradrenergic system, and that the cold stress-induced suppression of NK cytotoxicity might be mediated by the activation of peripheral sympathetic nerve.