Recent studies have shown that, in addition to being modulated by presynaptic facilitation, the sensory neurons of the gill- and siphon-withdrawal reflex of Aplysia are also capable of being modulated by transient presynaptic inhibition produced by the peptide Phe-Met-Arg-Phe-NH2. These two modulatory effects involve different second-messenger systems: the facilitation is mediated through cAMP-dependent protein phosphorylation, and the inhibition is mediated through the lipoxygenase pathway of arachidonic acid. To explore the behavioral function of this inhibition, we have carried out a parametric analysis of the effect of tail shock on the siphon-withdrawal reflex. In addition to producing sensitization of the withdrawal reflex, tail shock also transiently inhibits the reflex. The inhibition is produced by relatively weak shock, whereas sensitization is more prominent and may mask the inhibition with stronger shock. Furthermore, inhibition is not observed after habituation training. Cellular studies suggest that the behavioral inhibition is mediated, at least in part, by presynaptic inhibition of transmitter release from the siphon sensory neurons. Moreover, we have identified an interneuron within the left pleural ganglion (LPL16) that shows Phe-Met-Arg-Phe-NH2 immunoreactivity, is activated by tail shock, and simulates the presynaptic inhibitory actions produced by tail shock. Therefore, our results suggest that presynaptic inhibition mediated by Phe-Met-Arg-Phe-NH2 and its lipoxygenase second messenger contributes to behavioral inhibition of the siphon-withdrawal reflex.