Adaptation of the gastric mucosa to repeated administration of aspirin is a well-documented phenomenon, but the underlying mechanism is not fully understood. In this study, we tested the hypothesis that adaptation of the rat stomach to chronic aspirin administration required contact between the aspirin and the gastric mucosa. Rats were orally treated twice daily with either aspirin (100 mg/kg) or the vehicle. After various periods of treatment (< or = 20 days), the rats were given a higher dose of aspirin (250 mg/kg po), and the extent of gastric damage was assessed 3 h later. Rats receiving chronic aspirin demonstrated the development, in a time-dependent manner, of resistance to the damaging effects of aspirin. Chronic aspirin administration also significantly decreased the susceptibility of the rat stomach to damage induced by indomethacin or naproxen. The adaptation phenomenon was associated with a parallel increase in inflammatory infiltration of the mucosa, as measured by tissue myeloperoxidase activity and histology. Prostaglandin synthesis was markedly suppressed (> 80%) in all rats treated with aspirin. Gastric mucosal ornithine decarboxylase activity was not affected by chronic aspirin administration. If aspirin was administered subcutaneously or intrajejunally for 20 days, neither adaptation nor inflammation of the gastric mucosa was observed. These studies demonstrate that the rat stomach adapts to chronic oral administration of aspirin, but not to aspirin administration via other routes. Adaptation of the gastric mucosa occurred in parallel to infiltration of granulocytes. Whether these two phenomena are mechanistically or causally linked is not yet clear.