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Rapid optical control of nociception with an ion-channel photoswitch


Local anesthetics effectively suppress pain sensation, but most of these compounds act nonselectively, inhibiting activity of all neurons. Moreover, their actions abate slowly, preventing precise spatial and temporal control of nociception. We developed a photoisomerizable molecule, quaternary ammonium–azobenzene–quaternary ammonium (QAQ), that enables rapid and selective optical control of nociception. QAQ is membrane-impermeant and has no effect on most cells, but it infiltrates pain-sensing neurons through endogenous ion channels that are activated by noxious stimuli, primarily TRPV1. After QAQ accumulates intracellularly, it blocks voltage-gated ion channels in the trans form but not the cis form. QAQ enables reversible optical silencing of mouse nociceptive neuron firing without exogenous gene expression and can serve as a light-sensitive analgesic in rats in vivo. Because intracellular QAQ accumulation is a consequence of nociceptive ion-channel activity, QAQ-mediated photosensitization is a platform for understanding signaling mechanisms in acute and chronic pain.

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Figure 1: Intracellular QAQ photosensitized voltage-gated ion channels.
Figure 2: Intracellular QAQ as a photoswitchable inhibitor of neuronal activity.
Figure 3: TRPV1 channels and P2X7 receptors as a conduit for QAQ entry into cells.
Figure 4: Photosensitization of intact DRGs recorded with a three-dimensional multielectrode array (MEA).
Figure 5: Photosensitization of spinal cord slices.
Figure 6: QAQ optically regulated nociception in vivo, in live rats.

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We thank M.R. Banghart and M. Kienzler for helping synthesize QAQ, S. Scott for his help with computer programming, D. Bautista for helpful comments, A. Nicke (Max Planck Institute of Brain Research) for the P2X7 receptor clone, A. Blatz (Photoswitch Biosciences, Inc.) for HEK-293 cells stably expressing Cav2.2 and F. Ory for artistic input. This work was supported by US National Institutes of Health grants MH088484 to R.H.K. and PN2 EY018241 to R.H.K. and D.T. (the University of California Berkeley Nanomedicine Development Center) and by the Center for Integrated Protein Science, Munich to D.T.

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A.M. and R.H.K. wrote the paper. A.M., T.F., Y.L.F., C.M.S., F.N., D.T. and. R.H.K. designed experiments. AM., T.F., Y.L.F., C.M.S. and C.H. performed electrophysiological experiments and analyzed data. A.M. and D.D. performed in vivo experiments.

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Correspondence to Dirk Trauner or Richard H Kramer.

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Mourot, A., Fehrentz, T., Le Feuvre, Y. et al. Rapid optical control of nociception with an ion-channel photoswitch. Nat Methods 9, 396–402 (2012).

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