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    (S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology.

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    Name:
    Accepted-00006396-900000000-99 ...
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    Description:
    Final Accepted Manuscript
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    Author
    Moutal, Aubin
    Chew, Lindsey A
    Yang, Xiaofang
    Wang, Yue
    Yeon, Seul Ki
    Telemi, Edwin
    Meroueh, Seeneen
    Park, Ki Duk
    Shrinivasan, Raghuraman
    Gilbraith, Kerry B
    Qu, Chaoling
    Xie, Jennifer Y
    Patwardhan, Amol
    Vanderah, Todd W
    Khanna, May
    Porreca, Frank
    Khanna, Rajesh
    Show allShow less
    Affiliation
    Univ Arizona, Coll Med, Dept Pharmacol
    Issue Date
    2016-07
    Keywords
    CaV2.2
    CRMP2
    (S)-lacosamide
    Constellation pharmacology
    Calcium imaging
    Postoperative pain
    Neuropathic pain
    
    Metadata
    Show full item record
    Publisher
    LIPPINCOTT WILLIAMS & WILKINS
    Citation
    (S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology. 2016, 157 (7):1448-63 Pain
    Journal
    Pain
    Rights
    Copyright: © 2016 International Association for the Study of Pain.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Chronic pain affects the life of millions of people. Current treatments have deleterious side effects. We have advanced a strategy for targeting protein interactions which regulate the N-type voltage-gated calcium (CaV2.2) channel as an alternative to direct channel block. Peptides uncoupling CaV2.2 interactions with the axonal collapsin response mediator protein 2 (CRMP2) were antinociceptive without effects on memory, depression, and reward/addiction. A search for small molecules that could recapitulate uncoupling of the CaV2.2-CRMP2 interaction identified (S)-lacosamide [(S)-LCM], the inactive enantiomer of the Food and Drug Administration-approved antiepileptic drug (R)-lacosamide [(R)-LCM, Vimpat]. We show that (S)-LCM, but not (R)-LCM, inhibits CRMP2 phosphorylation by cyclin dependent kinase 5, a step necessary for driving CaV2.2 activity, in sensory neurons. (S)-lacosamide inhibited depolarization-induced Ca influx with a low micromolar IC50. Voltage-clamp electrophysiology experiments demonstrated a commensurate reduction in Ca currents in sensory neurons after an acute application of (S)-LCM. Using constellation pharmacology, a recently described high content phenotypic screening platform for functional fingerprinting of neurons that uses subtype-selective pharmacological agents to elucidate cell-specific combinations (constellations) of key signaling proteins that define specific cell types, we investigated if (S)-LCM preferentially acts on certain types of neurons. (S)-lacosamide decreased the dorsal root ganglion neurons responding to mustard oil, and increased the number of cells responding to menthol. Finally, (S)-LCM reversed thermal hypersensitivity and mechanical allodynia in a model of postoperative pain, and 2 models of neuropathic pain. Thus, using (S)-LCM to inhibit CRMP2 phosphorylation is a novel and efficient strategy to treat pain, which works by targeting specific sensory neuron populations.
    Note
    12 month embargo
    ISSN
    1872-6623
    PubMed ID
    26967696
    DOI
    10.1097/j.pain.0000000000000555
    Version
    Final accepted manuscript
    Sponsors
    Arizona Health Science Center; American Heart Association [SDG5280023]; Department of Defense Congressionally Directed Military Medical Research and Development Program [NF1000099]; Children's Tumor Foundation NF1 Synodos grant [2015-04-009A]; Children's Tumor Foundation; Flinn Scholarship; University of Arizona Undergraduate Biology Research Program; University of Arizona Undergraduate Honors College; University of Arizona Neuroscience and Cognitive Science Undergraduate fund; Medical Student Research Program from the National Institutes of Health
    Additional Links
    http://journals.lww.com/pain/Citation/2016/07000/_S__lacosamide_inhibition_of_CRMP2_phosphorylation.11.aspx
    ae974a485f413a2113503eed53cd6c53
    10.1097/j.pain.0000000000000555
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