(S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology.
Chew, Lindsey A
Yeon, Seul Ki
Park, Ki Duk
Gilbraith, Kerry B
Xie, Jennifer Y
Vanderah, Todd W
AffiliationUniv Arizona, Coll Med, Dept Pharmacol
MetadataShow full item record
PublisherLIPPINCOTT 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
RightsCopyright: © 2016 International Association for the Study of Pain
Collection InformationThis 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 email@example.com.
AbstractChronic 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.
Note12 month embargo
VersionFinal accepted manuscript
SponsorsArizona 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
CollectionsUA Faculty Publications
- (S)-Lacosamide Binding to Collapsin Response Mediator Protein 2 (CRMP2) Regulates CaV2.2 Activity by Subverting Its Phosphorylation by Cdk5.
- Authors: Moutal A, François-Moutal L, Perez-Miller S, Cottier K, Chew LA, Yeon SK, Dai J, Park KD, Khanna M, Khanna R
- Issue date: 2016 Apr
- A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors.
- Authors: François-Moutal L, Wang Y, Moutal A, Cottier KE, Melemedjian OK, Yang X, Wang Y, Ju W, Largent-Milnes TM, Khanna M, Vanderah TW, Khanna R
- Issue date: 2015 Jul
- Efficacy of (<i>S</i>)-Lacosamide in preclinical models of cephalic pain.
- Authors: Moutal A, Eyde N, Telemi E, Park KD, Xie JY, Dodick DW, Porreca F, Khanna R
- Issue date: 2016 Jun
- Sustained relief of ongoing experimental neuropathic pain by a CRMP2 peptide aptamer with low abuse potential.
- Authors: Xie JY, Chew LA, Yang X, Wang Y, Qu C, Wang Y, Federici LM, Fitz SD, Ripsch MS, Due MR, Moutal A, Khanna M, White FA, Vanderah TW, Johnson PL, Porreca F, Khanna R
- Issue date: 2016 Sep
- The functionalized amino acid (S)-Lacosamide subverts CRMP2-mediated tubulin polymerization to prevent constitutive and activity-dependent increase in neurite outgrowth.
- Authors: Wilson SM, Moutal A, Melemedjian OK, Wang Y, Ju W, François-Moutal L, Khanna M, Khanna R
- Issue date: 2014