Activation of planarian TRPA1 by reactive oxygen species reveals a conserved mechanism for animal nociception

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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 Drosophila flies are also defective in noxious-heat responses. We find that either planarian or human TRPA1 can restore noxious-heat avoidance to TRPA1-mutant Drosophila, although neither is directly activated by heat. Instead, our data suggest that TRPA1 activation is mediated by H2O2 and 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.

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We thank D. Tracey and R. Carthew for reagents; A. Kuang and L. Vinson for technical assistance; L. Macpherson, D. Yarmolinsky, and members of the Gallio Lab for comments on the manuscript; I. Raman for technical advice, and M. Stensmyr for the kind gift of the fly drawing in Fig. 1. Work in the Gallio lab is supported by NIH grant R01NS086859 (to M.G.), the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust (to E.E.Z.), and by training grant 2T32MH067564 (to O.M.A.). Work in the Petersen Lab is supported by an NIH Director’s New Innovator award (1DP2DE024365-01).

Author information


  1. Department of Neurobiology, Northwestern University, Evanston, IL, USA

    • Oscar M. Arenas
    • , Emanuela E. Zaharieva
    • , Alessia Para
    •  & Marco Gallio
  2. Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA

    • Constanza Vásquez-Doorman
    •  & Christian P. Petersen


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M.G. designed the study, analyzed the data, and wrote the paper with critical input from all authors; M.G. and O.M.A. designed and built the behavioral assays. O.M.A. performed all planarian behavioral experiments and electrophysiology and analyzed the corresponding data. E.E.Z. performed all fly rescue experiments and ROS assays and analyzed the corresponding data. A.P. cloned Smed-TRPA1, produced rescue constructs and transgenics, and analyzed sequences with help from C.P.P.; A.P., O.M.A., and C.V.D. performed q-PCR and ISH experiments. E.E.Z. and O.M.A. generated human-TRPA1-expressing flies.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Marco Gallio.

Integrated supplementary information.

Supplementary information.

  1. Supplementary Text and Figures

    Supplementary Figures 1–5

  2. Life Sciences Reporting Summary

  3. Supplementary Video 1

    The videos show heat avoidance behaviour of control worms as well as Smed-TRPA1 RNAi worms (S. mediterranea; videos are accelerated 24X). In this arena, worms are given a choice between 24°C (top right and bottom left tiles) and 32°C (top left and bottom right tiles). Control worms are essentially confined to the cool quadrants; in contrast Smed-TRPA1 RNAi planarians glide around the chamber but do not appear confined to the 24°C regions (i.e. they are defective in heat avoidance)

  4. Supplementary Video 2

    This set up consists of shallow circular chambers filled with water and interconnected by narrow corridors that worms do not readily traverse (note that connected chambers form an inverted U shape, i.e. chambers 1 at the bottom right and 4 at the bottom left do not communicate). At the beginning of each experiment, worms are introduced in chamber 1 in the presence of either a mock Agar pellet or of a pellet laced with AITC. AITC avoidance is apparent as the worms perform quick withdrawal manoeuvres in the vicinity of the AITC pellet and eventually escape to distant chambers (videos are accelerated 24X; Note that the setup used to acquire the data presented in Figure 2 was a simplified version, with two chambers rather than four)