To investigate human synovial mast cell physiology, we developed a model in which mast cells in human synovial explant cultures were activated by immunologic or non-immunologic mechanisms. Small (3 mm) cubes of synovial membrane were incubated with or without secretagogue for 30, 45 or 60 min, and supernatant histamine concentrations were quantified. We measured significant histamine release with compound 48/80 at concentrations > or = 1 mg/ml, and with calcium ionophore A23187 at > or = 5 micrograms/ml. Rabbit IgG anti-human IgE induced significant histamine release at all concentrations tested, maximum at 78 micrograms/ml. Morphine sulfate produced no histamine release from synovial explants, in contrast to its significant stimulation of histamine release from neonatal foreskin explants in our explant system. We confirmed synovial mast cell degranulation by electron microscopy, and showed that it corresponded with measurable histamine release. Furthermore, histamine release was not due to secretagogue-induced cytotoxicity, as assessed by supernatant lactate dehydrogenase levels and by ultrastructural analysis. Since morphine sulfate induces mast cell degranulation and histamine release in adult and neonatal human skin, our data show that although synovial and dermal mast cells have a similar granule enzyme profile and electron microscopic morphology, they differ in functional responses. These observations support recent data that among similar human mast cell subtypes there are physiologic differences. Finally, our explant model will be useful in studies of mast cell involvement in arthritis.