title: (S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology.
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.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Aubin
authors.initials: A
authors.lastname: Moutal
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Chew
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biological Chemistry, University of Science and Technology and Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors.forename: Seul Ki
authors.initials: SK
authors.lastname: Yeon
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Telemi
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Seeneen
authors.initials: S
authors.lastname: Meroueh
authors.affiliation: Department of Biological Chemistry, University of Science and Technology and Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors.forename: Ki Duk
authors.initials: KD
authors.lastname: Park
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Raghuraman
authors.initials: R
authors.lastname: Shrinivasan
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Kerry B
authors.initials: KB
authors.lastname: Gilbraith
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Chaoling
authors.initials: C
authors.lastname: Qu
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Xie
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Amol
authors.initials: A
authors.lastname: Patwardhan
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: May
authors.initials: M
authors.lastname: Khanna
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
mesh_terms: D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins; D000078334:Lacosamide; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D010149:Postoperative Pain / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000081:Acetamides; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C095114:collapsin response mediator protein-2; D000078334:Lacosamide