Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances

Capsaicin, a pungent ingredient of hot peppers, causes excitation of small sensory neurons, and thereby produces severe pain. A nonselective cation ch annel activated by capsaicin has been identified in sensory neurons and a c DNA encoding the channel has been cloned recently. However, an endogenous a ctivator of the receptor has not yet been found. In this study, we show tha t several products of lipoxygenases directly activate the capsaicin-activat ed channel in isolated membrane patches of sensory neurons. Among them, 12- and 15-(S)-hydroperoxyeicosatetraenoic acids, 5- and 15-(S)-hydroxyeicosat etraenoic acids, and leukotriene Bq possessed the highest potency. The eico sanoids also activated the cloned capsaicin receptor (VR1) expressed in HEK cells. Prostaglandins and unsaturated fatty acids failed to activate the c hannel. These results suggest a novel signaling mechanism underlying the pa in sensory transduction.