Bicarbonate secretion by duodenal mucosa free of Brunner's glands was titrated in situ in anesthetized rats. Intracerebroventricular infusion of thyrotropin-releasing hormone (0.01-1 microgram/h), bombesin, gastrin-releasing peptide, or corticotropin-releasing factor increased the bicarbonate secretion and the transmucosal electrical potential difference. The increase in secretion in response to thyrotropin-releasing hormone and bombesin was prevented by cervical vagotomy. Intravenous administration of the alpha-adrenoceptor antagonist phentolamine increased the magnitude and duration of the response, suggesting that these two peptides in addition to eliciting vagal stimulation of the duodenal secretion, by sympathetic activation, inhibit the secretion. Intravenous thyrotropin-releasing hormone (3.6 mg/kg) did not affect the secretion, further indicating that effects were elicited within the central nervous system. Intracerebroventricular infusion of cholecystokinin-octapeptide or beta-endorphin had no effect on duodenal bicarbonate secretion or on the potential difference. The latter peptide was a potent stimulant of the secretion when injected intravenously and probably acts at a peripheral site. The central nervous control of duodenal mucosal bicarbonate secretion is thus influenced by some specific peptides that are known to occur in brain tissue, and duodenal protection against acid might be modulated by agents affecting this control.