This study assessed the receptor site at which high systemic doses of epinephrine act to reduce the severity of adjuvant-induced arthritis in the rat. To this end we examined the effect of selective adrenergic antagonists on the reduction of arthritis by epinephrine, and also assessed whether high doses of selective adrenergic agonists mimicked the effect of epinephrine. The decrease in arthritis induced by epinephrine (0.5 mg/kg in chronic implant injected every 3 days) was significantly antagonized by the selective alpha 2-adrenergic antagonist, yohimbine, but not by selective alpha 1 (prazosin), beta 1 (metoprolol) or beta 2 (butoxamine) antagonists. In addition, chronic infusion of the alpha 2-adrenergic agonist clonidine, but not selective alpha 1 (phenylephrine), beta 1/beta 2 (isoproterenol) or beta 2 (salbutamol) agonists, resulted in decreased arthritis severity. These data suggest that the suppressive effect of high-dose epinephrine on joint injury in experimental arthritis is mediated by action at the alpha 2-adrenergic receptor.