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: 25.95). 02/2012; 9(4):396-402. DOI: 10.1038/nmeth.1897
Source: PubMed

ABSTRACT 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, Aug 15, 2015
    • "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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    ABSTRACT: In vivo pharmacology and optogenetics hold tremendous promise for dissection of neural circuits, cellular signaling, and manipulating neurophysiological systems in awake, behaving animals. Existing neural interface technologies, such as metal cannulas connected to external drug supplies for pharmacological infusions and tethered fiber optics for optogenetics, are not ideal for minimally invasive, untethered studies on freely behaving animals. Here, we introduce wireless optofluidic neural probes that combine ultrathin, soft microfluidic drug delivery with cellular-scale inorganic light-emitting diode (μ-ILED) arrays. These probes are orders of magnitude smaller than cannulas and allow wireless, programmed spatiotemporal control of fluid delivery and photostimulation. We demonstrate these devices in freely moving animals to modify gene expression, deliver peptide ligands, and provide concurrent photostimulation with antagonist drug delivery to manipulate mesoaccumbens reward-related behavior. The minimally invasive operation of these probes forecasts utility in other organ systems and species, with potential for broad application in biomedical science, engineering, and medicine. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 07/2015; DOI:10.1016/j.cell.2015.06.058
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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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    ABSTRACT: Ion channels are transmembrane proteins that control the movement of ions across the cell membrane. They are the molecular machines that make neurons excitable by enabling the initiation and propagation of action potentials (APs). Rapid signaling within and between neurons requires complex molecular processes that couple the sensing of membrane voltage or neurotransmitter release to the fast opening and closing of the ion channel gate. Malfunction of an ion channel's sensing or gating module can have disastrous pathological consequences. However, linking molecular changes to the modulation of neural circuits and ultimately to a physiological or pathological state is not a straightforward task. It requires precise and sophisticated methods of controlling the function of ion channels in their native environment. To address this issue we have developed new photochemical tools that enable the remote control of neuronal ion channels with light. Due to its optical nature, our approach permits the manipulation of the nervous system with high spatial, temporal and molecular precision that will help us understand the link between ion channel function and physiology. In addition, this strategy may also be used in the clinic for the direct treatment of some neuronal disorders.
    Frontiers in Molecular Neuroscience 03/2013; 6:5. DOI:10.3389/fnmol.2013.00005
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    ABSTRACT: A diimine ligand, LL = 2-C5H4NCH=N-4-C6H4N=NPh, which carries a trans-azobenzene substituent, forms the dimethylplatinum(II) complex [PtMe2(LL)], which undergoes trans oxidative addition with MeI, PhCH2Br, Br-2, and I-2 to give the corresponding organoplatinum(IV) complexes [PtIMe3(LL)], [PtBrMe2(CH2Ph)(LL)], [PtBr2Me2(LL)], and [PtI2Me2(LL)], respectively. The ligand and the platinum(II) and platinum(IV) complexes are shown to undergo trans-cis isomerization of the azobenzene substituent upon irradiation, and the cis isomers then underwent slow thermal isomerization back to the more stable trans isomers.
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