期刊
PAIN
卷 157, 期 7, 页码 1448-1463出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/j.pain.0000000000000555
关键词
CaV2.2; CRMP2; (S)-lacosamide; Constellation pharmacology; Calcium imaging; Postoperative pain; Neuropathic pain
资金
- 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
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 Ca2+ influx with a low micromolar IC50. Voltage-clamp electrophysiology experiments demonstrated a commensurate reduction in Ca2+ 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.
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