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

Aubin Moutal, Lindsey A. Chew, Xiaofang Yang, Yue Wang, Seul Ki Yeon, Edwin Telemi, Seeneen Meroueh, Ki Duk Park, Raghuraman Shrinivasan, Kerry B. Gilbraith, Chaoling Qu, Jennifer Y. Xie, Amol Patwardhan, Todd W. Vanderah, May Khanna, Frank Porreca, Rajesh Khanna

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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 2+ influx with a low micromolar IC 50. Voltage-clamp electrophysiology experiments demonstrated a commensurate reduction in Ca 2+ 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.

Original languageEnglish (US)
Pages (from-to)1448-1463
Number of pages16
JournalPain
Volume157
Issue number7
DOIs
StatePublished - Jul 1 2016
Externally publishedYes

Keywords

  • (S)-lacosamide
  • Calcium imaging
  • CaV2.2
  • Constellation pharmacology
  • CRMP2
  • Neuropathic pain
  • Postoperative pain

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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