cover image: A photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals

A photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals

1 Dec 2023

Abstract By endowing light control of neuronal activity, optogenetics and photopharmacology are powerful methods notably used to probe the transmission of pain signals. However, costs, animal handling and ethical issues have reduced their dissemination and routine use. Here we report LAKI (Light Activated K + channel Inhibitor), a specific photoswitchable inhibitor of the pain-related two-pore-domain potassium TREK and TRESK channels. In the dark or ambient light, LAKI is inactive. However, alternating transdermal illumination at 365 nm and 480 nm reversibly blocks and unblocks TREK/TRESK current in nociceptors, enabling rapid control of pain and nociception in intact and freely moving mice and nematode. These results demonstrate, in vivo, the subcellular localization of TREK/TRESK at the nociceptor free nerve endings in which their acute inhibition is sufficient to induce pain, showing LAKI potential as a valuable tool for TREK/TRESK channel studies. More importantly, LAKI gives the ability to reversibly remote-control pain in a non-invasive and physiological manner in naive animals, which has utility in basic and translational pain research but also in in vivo analgesic drug screening and validation, without the need of genetic manipulations or viral infection.

Authors

Arnaud Landra-Willm, Ameya Karapurkar, Alexia Duveau, Anne Amandine Chassot, Lucille Esnault, Gerard Callejo, Marion Bied, Stephanie Häfner, Florian Lesage, Brigitte Wdziekonski, Anne Baron, Pascal Fossat, Laurent Marsollier, Xavier Gasull, Eric Boué-Grabot, Michael Kienzler, Guillaume Sandoz

Bibliographic Reference
Arnaud Landra-Willm, Ameya Karapurkar, Alexia Duveau, Anne Amandine Chassot, Lucille Esnault, et al.. A photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals. Nature Communications, 2023, 14 (1), pp.1160. ⟨10.1038/s41467-023-36806-4⟩. ⟨inserm-04012034⟩
DOI
https://doi.org/10.1038/s41467-023-36806-4
HAL Collection
['INSERM - Institut national de la santé et de la recherche médicale', 'Université Nice Sophia Antipolis', 'CNRS - Centre national de la recherche scientifique', "Université d'Angers", "Université Côte d'Azur", 'Sorbonne Université', 'Faculté des Sciences de Sorbonne Université', 'Sorbonne Université - Texte Intégral', 'Alliance Sorbonne Université', 'Institut de pharmacologie moléculaire et cellulaire', 'Immunologie et nouveaux concepts en immunothérapie/Immunology and New Concepts in Immuno-Therapy', 'Nantes Université', 'Fondation pour la Recherche Médicale', 'UFR de médecine - Nantes Université']
HAL Identifier
4012034
Institution
['University of Maine', 'Université de Bordeaux', "Université d'Angers", 'Institut National de la Santé et de la Recherche Médicale', 'Centre hospitalier universitaire de Nantes', 'Nantes Université - pôle Santé', 'Universitat de Barcelona', 'Centre Hospitalier Universitaire de Nice', 'Université Nice Sophia Antipolis (1965 - 2019)', 'University of Connecticut']
Laboratory
['Institut des Maladies Neurodégénératives [Bordeaux]', 'Immunology and New Concepts in ImmunoTherapy', 'Institut de pharmacologie moléculaire et cellulaire']
Published in
France

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