To assess the possible role of urocortin, a recently identified neuropeptide related to corticotropin-releasing factor (CRF), in modulation of peripheral immune functions, the effects of intracranially administrated urocortin on the proliferative activity of splenic lymphocytes were examined in rats. Intracerebroventricular (i.c.v.) injection of urocortin (1 ng) produced a marked decrease in the proliferative response of splenocytes to a mitogen. The suppressive effect of urocortin was abolished by pretreatment with a ganglionic blocking agent (chlorisondamine) or β-adrenergic receptor antagonist (propranolol), but not by adrenalectomy. These results suggest that urocortin is an important neuropeptide involved in the brain control of peripheral immune functions such as stress-induced immunosuppression, and that the suppressive effect of urocortin is mediated by the sympathetic nervous system.