Rapid optical control of nociception with an ion channel photoswitch

Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA.
Nature Methods (Impact Factor: 32.07). 02/2012; 9(4):396-402. DOI: 10.1038/nmeth.1897
Source: PubMed


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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Available from: Alexandre Mourot
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    • "Optopharmacological agents have been enthusiastically received in neuroscience for in vitro applications (Banghart and Sabatini, 2012; Callaway and Katz, 1993; Carter and Sabatini, 2004; Matsuzaki et al., 2001), but their use in vivo has been limited. Although compelling findings exist addressing the external visual nervous system and the surface of the cortex (Mourot et al., 2012; Noguchi et al., 2011; Polosukhina et al., 2012; Tochitsky et al., 2014), optopharmacological application in the deep brain remains a significant challenge. Optofluidic devices that provide access to the UV spectrum with advanced m-ILEDs could target these highly selective photosensitive tools to spatially isolated regions of the central nervous system in nongenetically altered mammals. "
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    • "However, subsequent work indicated that PCLs enter the cell and photosensitize a wide range of voltage-gated channels via the internal TEA site (Banghart et al., 2009; Fehrentz et al., 2012). Most notably, such compounds have been used for photocontrol of ion channels in the retina for vision restoration in blind mice (Tochitsky et al., 2012) and for optically controlled analgesia via a PCL called quaternary ammonium-azobenzene-quaternary ammonium (QAQ) that specifically enters nociceptive ion channel-expressing cells (Mourot et al., 2012). However, despite their power for control of membrane potential, in most cases PCLs lack target specificity which makes it difficult to determine a particular channel’s contribution. "
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    • "Shaker a K b v Na b, c v L-type Ca c v 367 4 min f, j 20–30 Banghart, 2009; Banghart et al., 2009 PrAQ Shaker a 338 13 min f, j 40 Banghart, 2009; Banghart et al., 2009 DENAQ K v 3.1 a K v 2.1 a, f K v 4.2 a, f K b, f v Shaker a K ir 2.1 a, f Ca v 2.2 a, f Na f v 470 300 ms k 100 Mourot et al., 2011 PhENAQ Shaker a K v 3.1 a, f K b v 456 160 ms to 2.6 s k 20–50 Mourot et al., 2011 QAQ Shaker a K v 2.1 a K v 3.1 a K v 4.2 a K b, i v Na b, g, h, i v Na v 1.5 a, f Ca v 2.2 a L-type Ca c v K ir 2.1 a HCN g iGluR b 362 7 min j 100–300 l Banghart et al., 2009; Mourot et al., 2012 "
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