Pergolide, a dopamine agonist effective in the treatment of Parkinson's disease, has been shown to have anti-inflammatory activity in the carrageenan paw edema assay in rats at p.o. doses greater than or equal to 0.3 mg/kg. Studies were done to investigate the mechanism of action and to determine the pharmacologic significance of this finding. Because pergolide elevates circulating glucocorticoids, the effect of pergolide on carrageenan-induced paw swelling was assessed in adrenalectomized rats. Pergolide retained its anti-inflammatory activity in adrenalectomized carrageenan-injected rats, thus eliminating corticosterone induction as a possible mechanism of action. Pergolide treatment also did not decrease thromboxane B2, prostaglandin E2 or leukotriene B4 production, ruling out direct effects on arachnoid acid inflammatory mediators. Interactions with the autonomic nervous system were suggested, in that an alpha adrenergic agonist (clonidine) mimicked the activity of pergolide in the carrageenan assay, and an alpha adrenergic antagonist (phenoxybenzamine) blocked the anti-inflammatory activity of pergolide in this assay. Dopamine receptor antagonists (haloperidol or sulpiride) partially inhibited the effect of pergolide in the carrageenan model. However, the peripherally restricted dopamine antagonist, domperidone, was ineffective, suggesting that a central dopamine receptor was involved in the effect. Experiments in chronic inflammation models such as lipoidal-amine induced arthritis in rats and picryl chloride-induced delayed type hypersensitivity in mice also revealed an anti-inflammatory effect of pergolide. Activity in the carrageenan system and the lipoidalamine model demonstrated that the anti-inflammatory effects of pergolide were separable from potential immunosuppressive effects. Multiple dose studies indicated that tolerance might develop to the anti-inflammatory effect of pergolide.(ABSTRACT TRUNCATED AT 250 WORDS)