All animals must detect noxious stimuli to initiate protective behavior, but the evolutionary origin of nociceptive systems is not well understood. Here, we show that noxious heat and irritant chemicals elicit robust escape behaviors in the planarian Schmidtea mediterranea, and that the conserved ion channel TRPA1 is required for these responses. TRPA1 mutant flies (Drosophila) are also defective in noxious heat responses. Unexpectedly, we find that either planarian or human TRPA1 can restore noxious heat avoidance to TRPA1 mutant Drosophila, even though neither is directly activated by heat. Instead, our data suggest that TRPA1 activation is mediated by H2O2/Reactive Oxygen Species, early markers of tissue damage rapidly produced as a result of heat exposure. Together, our data reveal a core function for TRPA1 in noxious heat transduction, demonstrate its conservation from planarians to humans, and imply that animal nociceptive systems may share a common ancestry, tracing back to a progenitor that lived more than 500 million years ago.

Highlights d Catnip is a broad-acting insect repellent d The repellency is mediated via iridoids such as nepetalactone d Catnip and nepetalactone activate select insect TRPA1 isoforms d TRPA1-deficient mosquitoes show no aversion to catnip

Fc gamma receptor polymorphisms as predictive markers of Cetuximab efficacy in epidermal growth factor receptor downstream-mutated metastatic colorectal cancer. Eur. J. Cancer 48, 1774-1780.

All animals must detect noxious stimuli to initiate protective behavior, but the evolutionary origin of nociceptive systems is not well understood. Here, we show that a remarkably conserved signaling mechanism mediates the detection of noxious stimuli in animals as diverse as flatworms and humans. Planarian flatworms are amongst the simplest bilateral animals with a centralized nervous system, and capable of directed behavior. We demonstrate that noxious heat and irritant chemicals elicit robust escape behaviors in the planarian Schmidtea mediterranea, and that the conserved ion channel TRPA1 is required for these responses. TRPA1 mutant fruit flies (Drosophila) are also defective in the avoidance of noxious heat [1][2][3] . Unexpectedly, we find that either the planarian or the human TRPA1 can restore noxious heat avoidance to TRPA1 mutant Drosophila, even though neither is directly activated by heat. Instead, our data suggest that TRPA1 activation is mediated by H 2 O 2 /Reactive Oxygen Species, early markers of tissue damage rapidly produced as a result of heat exposure. Together, our data reveal a core function for TRPA1 in noxious heat transduction, demonstrate its conservation from planarians to humans, and imply that human nociceptive systems may share a common ancestry with those of most extant animals, tracing back their origin to a progenitor that lived more than 500 million years ago.