Thyrotropin-releasing hormone (TRH) is a central nervous system (CNS) transmitter that stimulates various gastrointestinal secretory and motor processes by increasing vagal outflow. In this study, the CNS effects of TRH on ileal and jejunal water transport were examined in awake rats and dogs, respectively. Cerebral but not intravenous TRH (0.1-5.0 nmol/kg) significantly (P < 0.01) reversed net water absorption from approximately 30 microliters.cm-1.h-1 in rats and 300 microliters.cm-1.h-1 in dogs toward net water secretion of 60 and 600 microliters.cm-1.h-1, respectively. Truncal vagotomy and ganglionic blockade with chlorisondamine completely abolished this stimulatory effect of cerebral TRH, whereas adrenalectomy, hypophysectomy, noradrenergic and opiate blockade, and inhibition of prostaglandin and nitric oxide synthesis did not. Atropine methylnitrate significantly (P < 0.05) attenuated the stimulatory response produced by TRH by approximately 30%. Intravenous infusion of the vasoactive intestinal peptide (VIP) receptor antagonist, [4Cl-D-Phe6, Leu17]VIP (0.05-5.0 mumol.kg-1.h-1), significantly (P < 0.01) inhibited the stimulatory response of TRH by approximately 60%. Pretreatment of the animals with both atropine and the VIP antagonist completely abolished ileal and jejunal water secretion stimulated by cerebral TRH. These results indicate that 1) TRH acts within the CNS to stimulate net ileal and jejunal water secretion in rats and dogs, respectively; 2) these actions are mediated by vagal pathways; and 3) stimulation of intestinal secretion by cerebral TRH is primarily mediated by a VIP-sensitive mechanism and, in part, by a muscarinic mechanism.