A study was designed to examine the interactions of reserpine and morphine on rat intestinal transit. Intestinal transit was determined in adult male rats by measuring the progression of an intraduodenally administered bolus (0.2 ml) or radioactive chromium (Na2(51)CrO4, 0.5 microCi) solution through the small intestine. Reserpine phosphate and morphine sulfate were administered either s.c. at 5 mg/kg or intracerebroventricularly (i.c.v.) at 50 and 30 micrograms (total dose), respectively. Reserpine given s.c. 16 hr before testing enhanced intestinal transit when given alone and diminished the intestinal antipropulsive effects of morphine given s.c. or i.c.v. Reserpine given i.c.v. 8 hr before testing did not alter the intestinal effects of morphine given s.c. or i.c.v. Neostigmine methylsulfate (0.1 mg/kg) given s.c. did not alter intestinal transit by itself but antagonized the inhibition of intestinal transit produced by morphine given s.c. Atropine sulfate (6 mg/kg) given s.c. did not affect intestinal transit by itself, nor did it antagonize the intestinal effects of s.c. administered morphine. However, atropine inhibited enhanced intestinal transit after reserpine given s.c. and restored the inhibitory effect of peripheral morphine on intestinal transit in animals pretreated with peripheral neostigmine or reserpine. The results suggest that reserpine inhibits the central and peripheral antidiarrheal effects of morphine by acting peripherally. Reserpine may antagonize the intestinal antipropulsive effects of morphine in the rat by directly or indirectly activating muscarinic cholinergic receptors.