Studies of the marine mollusk Aplysia californica indicate that products of the 12-lipoxygenase pathway may be involved in neuronal intracellular signaling. The nervous tissue of Aplysia has a 12-lipoxygenase activity that converts both exogenous and endogenous arachidonic acid to an array of products, which include 12-hydroperoxyeicosatetraenoic acid (12-HPETE) and its metabolites hepoxilin A3, hepoxilin B3, 12-ketoeicosatetraenoic acid, and 12-oxododecatrienoic acid. These eicosanoids were identified using a combination of high-performance liquid chromatography, ultraviolet spectrometry and gas chromatography-mass spectrometry. Generation of 12-lipoxygenase products was stimulated by application of the neurotransmitters, histamine and FMRF-amide, or by stimulation of identified neural cells. In electrophysiological studies of identified L14 and sensory neurons it was found that 12-HPETE and its metabolic products exert physiological actions that resemble those of histamine and FMRF-amide. These results suggest that products of 12-HPETE metabolism may act as second messengers in Aplysia neurons.