In this study, we evaluated the effect of histamine on phasic contractile activity in the opossum sphincter of Oddi (SO). SO manometry was done in 35 animals, using an infused catheter system with minimal compliance. In anesthetized animals, phasic SO contractions occurred at a frequency of 7.3 +/- 0.3 (SE) contractions/min with an amplitude of 83 +/- 4 mmHg. Intravenous histamine (5-80 micrograms/kg) invariably inhibited the frequency and amplitude of SO phasic contractions. At larger doses, the SO contractions were abolished for several minutes. The SO inhibitory effect of histamine was duplicated by the selective H1-agonist, 2-pyridylethylamine, and abolished by H1-blockade with pyrilamine or neural blockade with tetrodotoxin. After tetrodotoxin, histamine and 2-pyridylethylamine caused an increased frequency and amplitude of SO contractions. This excitatory effect was blocked by pyrilamine. The histamine effects on SO phasic contractions were not altered by metiamide, atropine, phentolamine, propranolol, hexamethonium, or a large dose of nicotine. We conclude that 1) histamine depresses phasic SO contractions in the opossum; 2) histamine's depressant SO effect is mediated by H1 stimulation of noncholinergic, nonadrenergic SO inhibitory nerves, overriding an H1 stimulatory effect on SO smooth muscle; and 3) histamine has no H2-mediated effect on the opossum SO.