The stereospecificity of the action of opiates on rat mast cells was investigated by means of the l- and d-isomers levorphanol and dextrorphan. The dose-response curves for histamine release induced by the 2 drugs were of a similar shape with a maximum at 2 X 10(-3) M and a pronounced minimum at 5 X 10(-3) M. At concentrations below 5 X 10(-3) M the effect of both drugs resembled that of morphine, i.e. the release occurred rapidly and inhibition was observed with naloxone, codeine, and antimycin A. Levorphanol, dextrorphan, and the antagonist levallorphan at concentrations above 5 X 10(-3) M seemed to be toxic to mast cells. The uptake of 45Ca in connection with histamine release induced by pethidine, levorphanol, and dextrorphan was lower than that of control cells, whereas the uptake induced by morphine did not differ from that of controls. The inhibition of compound 48/80-induced histamine release by morphine was paralleled by a reduced 45Ca uptake. The time course for the inhibitory effect of preincubation with morphine was similar for the histamine released induced by morphine and by compound 48/80. Washing of the cells after preincubation with morphine was without effect on the inhibition of morphine-induced histamine release, whereas the inhibition of compound 48/80 was reduced. The present observation with morphine and compound 48/80 support our previous impression of similarities in their mode of action, but a mechanism implying an interference by morphine with the disposition of calcium could also account for the findings. The observed antagonism between morphine and calcium resembles that of opiate receptors, but histamine release induced by opiates does not involve stereospecific opiate receptors.