The previous demonstration of sigma receptors localized in the mucosa and the submucosal plexus of the duodenum led us to investigate the activity of two specific sigma (sigma H) receptor ligands, di (ortho-tolyl) guanidine (DTG) and (+) N-allyl normetazocine (d-NANM) on the alkaline secretion of the duodenum in anesthetized rats. DTG (0.25-2 mg/kg, i.v.) and d-NANM (0.5-5 mg/kg, i.v.) induced a dose-related increase of bicarbonate output, from a basal level of 7.6 +/- 0.1 microEq/cm/hr to a stimulated plateau of 14.1 +/- 0.2 and 14.2 +/- 0.2 microEq/cm/hr, respectively, for the next 2 hr. In contrast, the venous injection of I-NANM (5 mg/kg) did not significantly stimulate duodenal bicarbonate output. Intravenous administration of naloxone (0.2 mg/kg) failed to modify the response to both DTG and d-NANM, whereas haloperidol (0.5 mg/kg, i.v.) abolished the response to both drugs. The response to DTG was unchanged after indomethacin (0.25 mg/kg), yohimbine (2 mg/kg), atropine (1 mg/kg), sulpiride (1 mg/kg) or SCH 23,390 (0.45 mg/kg), and partly decreased after prazosin (1 mg/kg). Hexamethonium (1 mg/kg), and tetrodotoxin (5 micrograms/kg) reduced the response to DTG, respectively, by 79% (P less than 0.01) and 91% (P less than 0.01), whereas bilateral vagotomy suppressed it. The cholecystokininA receptor antagonist (-)L364,718 decreased the response to DTG by 91% (P less than 0.01). None of the antagonists changed the basal bicarbonate output but vagotomy, which induced a 52% (P less than 0.01) decrease.(ABSTRACT TRUNCATED AT 250 WORDS)