Plant-derived irritants are unique tools for studying receptor mechanisms in sensory neurons. Systematic studies of capsaicins, the pungent principals derived from the genus Capsicum, led to the discovery ad characterization of a capsaicin receptor mechanism in sensory neurons and afforded several molecular probes for studying the cellular and systemic basis of pain and irritation. Pungent compounds derived from plants used in Asian medicine that evoke qualitatively different from capsaicins sensations have so far not been investigated. We have found that this class of chemical irritants, unsaturated alkylamides, activates a subset of sensory neurons that is different from, although partly overlapping with, the population of neurons sensitive to capsaicin. Our finding that some of the neurons stimulated by these irritants are mechanosensitive may explain the noxious sensation of tingling, to which they give rise. This sensation is similar to that observed as a side effect of certain drugs and in certain peripheral pathologies. Our hypothesis, derived from preliminary results, is that these irritants activate unique subsets of sensory neurons by triggering sensory mechanisms, the identity and distribution of which have not been described yet. Therefore, these compounds and their analogs will be important tools for inducing abnormal sensations or paresthesias such as tingling and studying the neural basis of this sensory mechanism. Studies aimed at the identification of the neural pathways, neural coding and cellular mechanisms underlying these paresthesias would be greatly advanced with the availability of appropriate novel stimuli. Two of the goals of this project will be to create the first library of chemosensory irritants derived from Asian plants and synthesize analogs of the active compounds. The third goal will be to study the activity of the novel natural irritants and their synthetic analogs using the digital fluorescent determination of intracellular calcium in trigeminal sensory neurons in vitro, trigeminal nerve recordings in vivo and in artificial lipid bilayers. This research could lead to novel molecular tools for studying sensory neurons and elucidating new chemoreceptive pathways.