(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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Author
Moutal, AubinChew, 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
Affiliation
Univ Arizona, Coll Med, Dept PharmacolIssue Date
2016-07Keywords
CaV2.2CRMP2
(S)-lacosamide
Constellation pharmacology
Calcium imaging
Postoperative pain
Neuropathic pain
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LIPPINCOTT WILLIAMS & WILKINSCitation
(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 PainJournal
PainRights
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 embargoISSN
1872-6623PubMed ID
26967696Version
Final accepted manuscriptSponsors
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 HealthAdditional Links
http://journals.lww.com/pain/Citation/2016/07000/_S__lacosamide_inhibition_of_CRMP2_phosphorylation.11.aspxae974a485f413a2113503eed53cd6c53
10.1097/j.pain.0000000000000555
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