Chemical nociception, the detection of tissue-damaging chemicals, is important for animal survival and causes human pain and inflammation, but its evolutionary origins are largely unknown. Reactive electrophiles are a class of noxious compounds humans find pungent and irritating, like allyl isothiocyanate (in wasabi) and acrolein (in cigarette smoke)1–3. Insects to humans find reactive electrophiles aversive1–3, but whether this reflects conservation of an ancient sensory modality has been unclear. Here we identify the molecular basis of reactive electrophile detection in flies. We demonstrate that dTRPA1, the Drosophila melanogaster ortholog of the human irritant sensor, acts in gustatory chemosensors to inhibit reactive electrophile ingestion. We show that fly and mosquito TRPA1 orthologs are molecular sensors of electrophiles, using a mechanism conserved with vertebrate TRPA1s. Phylogenetic analyses indicate invertebrate and vertebrate TRPA1s share a common ancestor that possessed critical characteristics required for electrophile detection. These findings support emergence of TRPA1-based electrophile detection in a common bilaterian ancestor, with widespread conservation throughout vertebrate and invertebrate evolution. Such conservation contrasts with the evolutionary divergence of canonical olfactory and gustatory receptors and may relate to electrophile toxicity. We propose human pain perception relies on an ancient chemical sensor conserved across ~500 million years of animal evolution.

Discriminating among sensory stimuli is critical for animal survival. This discrimination is particularly essential when evaluating whether a stimulus is noxious or innocuous. From insects to humans, TRP channels are key transducers of thermal, chemical and other sensory cues1, 2. Many TRPs are multi-modal receptors that respond to diverse stimuli1–3, but how animals distinguish sensory inputs activating the same TRP is largely unknown. Here we determine how stimuli activating Drosophila TRPA1 are discriminated. While Drosophila TRPA1 responds to both noxious chemicals4 and innocuous warming5, we find that TRPA1-expressing chemosensory neurons respond to chemicals but not warmth, a specificity conferred by a chemosensory-specific TRPA1 isoform with reduced thermosensitivity compared to the previously described isoform. At the molecular level, this reduction results from a unique region that robustly reduces the channel’s thermosensitivity. Cell-type segregation of TRPA1 activity is critical: when the thermosensory isoform is expressed in chemosensors, flies respond to innocuous warming with regurgitation, a nocifensive response. TRPA1 isoform diversity is conserved in malaria mosquitoes, suggesting similar mechanisms may allow discrimination of host-derived warmth, an attractant, from chemical repellents. These findings indicate that reducing thermosensitivity can be critical for TRP channel functional diversification, facilitating their use in contexts where thermal sensitivity can be maladaptive.

Behavioral responses to temperature are critical for survival, and animals from insects to humans show strong preferences for specific temperatures1, 2. Preferred temperature selection promotes avoidance of adverse thermal environments in the short-term and maintenance of optimal body temperatures over the long-term1, 2, but its molecular and cellular basis is largely unknown. Recent studies have yielded conflicting views of thermal preference in Drosophila, attributing importance to either internal3 or peripheral4 warmth sensors. Here we reconcile these views by demonstrating that thermal preference is not a singular response, but involves multiple systems relevant in different contexts. We previously found that the Transient Receptor Potential (TRP) channel TRPA1 acts internally to control the slowly developing preference response of flies exposed to a shallow thermal gradient3. Here we find that the rapid response of flies exposed to a steep warmth gradient does not require TRPA1; rather, the Gustatory receptor (Gr) Gr28b(D) drives this behavior via peripheral thermosensors. Grs are a large gene family widely studied in insect gustation and olfaction and implicated in host-seeking by insect disease vectors5–7, but not previously implicated in thermosensation. At the molecular level, Gr28b(D) misexpression confers thermosensitivity upon diverse cell types, suggesting it is a warmth sensor. These data reveal a new type of thermosensory molecule and uncover a functional distinction between peripheral and internal warmth sensors in this tiny ectotherm reminiscent of thermoregulatory systems in larger, endothermic animals2. The use of multiple, distinct molecules to respond to a given temperature, as observed here, may facilitate independent tuning of an animal’s distinct thermosensory responses.

The pit organs of pit vipers, pythons, and boas are remarkable sensory devices that allow these snakes to detect infrared radiation emitted by warm-blooded prey. It has been theorized that this capacity reflects the pit organ's exceptional sensitivity to subtle fluctuations in temperature, but the molecules responsible for this extreme thermal resolution have been unknown. New evidence shows that pit organs respond to temperature using the warmth-activated cation channel TRPA1 (transient receptor potential ankyrin 1), a finding that provides a first glimpse of the underlying molecular hardware. The properties of these snake TRPA1s raise intriguing questions about the mechanisms responsible for the exceptional sensitivity of many biological thermoreceptors and about the evolutionary origins of these warmth-activated TRP channels.

Tobacco manufacturers successfully developed objective, EEG-based techniques to evaluate the influence of product characteristics on acceptance and use. Internal results suggest that complex interactions between pharmacological, sensory and behavioural factors mediate the brain changes that occur with smoking. These findings have implications for current proposals regarding the regulation of tobacco products and argue for the incorporation of objective measures of product effects when evaluating the health risks of new and existing tobacco products.