title: Rapid optical control of nociception with an ion-channel photoswitch.
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.
authors.affiliation: Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mourot
authors.forename: Timm
authors.initials: T
authors.lastname: Fehrentz
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Feuvre
authors.forename: Caleb M
authors.initials: CM
authors.lastname: Smith
authors.forename: Christian
authors.initials: C
authors.lastname: Herold
authors.forename: Deniz
authors.initials: D
authors.lastname: Dalkara
authors.forename: Frédéric
authors.initials: F
authors.lastname: Nagy
authors.forename: Dirk
authors.initials: D
authors.lastname: Trauner
authors.forename: Richard H
authors.initials: RH
authors.lastname: Kramer
mesh_terms: D000818:Animals; D001391:Azo Compounds / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D009411:Nerve Endings / Q000187:drug effects / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D059225:Nociception / Q000187:drug effects* / Q000528:radiation effects*; D010775:Photic Stimulation; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D050916:TRPV Cation Channels / Q000378:metabolism; D013997:Time Factors
chemical_list: D001391:Azo Compounds; D007473:Ion Channels; D017319:Photosensitizing Agents; D000644:Quaternary Ammonium Compounds; D058486:Receptors, Purinergic P2X7; D050916:TRPV Cation Channels; C009850:azobenzene