The present study was undertaken to determine the effect of iontophoretic applications of epinephrine (E) and its derivative alpha-methylepinephrine (mE) on the discharges of sympathetic preganglionic neurons (SPNs). Spontaneously active SPNs located in thoracic segment T2 were antidromically identified in White Carneaux pigeons anesthetized with urethane and immobilized with purified alpha-cobratoxin. All SPNs tested were inhibited by E, mE, several other catecholamines, clonidine, GABA, glycine and morphine. The inhibitory effects of E and mE but not those of GABA were antagonized by iontophoretic applications of the preferential alpha 2-antagonists piperoxane and yohimbine, but not by the alpha 1-antagonist prazosin or the beta-antagonist sotalol when similarly applied. The inhibitory effects of GABA, glycine and morphine were respectively antagonized by bicuculline methiodide, strychnine and naloxone, but these antagonists failed to alter the action of E. It is concluded that (1) epinephrine and its alpha-methyl derivative inhibit the discharges of SPNs via the activation of alpha 2-receptors and (2) the epinephrine-induced inhibition does not result from the secondary release of GABA, glycine or opioid peptides from afferent terminals or interneurons.