Anyone who has become teary-eyed cutting an onion, caught a whiff of wasabi, or tasted the spiciness of cinnamon, has experienced, first-hand, the painful potential of chemicals. Numerous plants and animals rely on damaging chemicals to ward off predators, and environmental, chemical irritants have been implicated in human inflammatory disorders, such as asthma. Studying how animals detect and avoid noxious chemicals - a process known as chemical nociception - may be useful for the design of effective pest repellents and for understanding how painful stimuli are processed in humans. In both vertebrates and invertebrates, the Transient Receptor Potential (TRP) ion channels cooperate during many aspects of nociception;however, the nature of this cooperation is poorly characterized. In Drosophila, two TRP channels - Painless and dTRPA1 - are required for flies to avoid reactive electrophiles, pungent chemicals active in wasabi, cinnamon, and cigarette smoke. dTRPA1 functions as a molecular sensor for these compounds, but Painless is unlikely to be a direct chemical sensor, making its role during this form of nociception unclear. The goal of this proposal is to characterize the function of Painless during dTRPA1- mediated chemical nociception. This work will contribute to our understanding of how TRP channels cooperate during nociception and will provide insights into the mechanisms of pain signaling at the molecular, cellular and circuit levels. PUBLIC HEALTH RELEVANCE: Transient Receptor Potential (TRP) ion channels participate during pain signaling in animals ranging from insects to humans. In humans, TRP channels may contribute to chronic pathological pain conditions while insect-specific TRPs represent targets for controlling disease-carrying pests. For these reasons, understanding how TRP channels interact at the molecular, cellular and circuit levels has important implications for human health and is the primary goal of this research.