title: Sustained relief of ongoing experimental neuropathic pain by a CRMP2 peptide aptamer with low abuse potential.
abstract: Uncoupling the protein-protein interaction between collapsin response mediator protein 2 (CRMP2) and N-type voltage-gated calcium channel (CaV2.2) with an allosteric CRMP2-derived peptide (CBD3) is antinociceptive in rodent models of inflammatory and neuropathic pain. We investigated the efficacy, duration of action, abuse potential, and neurobehavioral toxicity of an improved mutant CRMP2 peptide. A homopolyarginine (R9)-conjugated CBD3-A6K (R9-CBD3-A6K) peptide inhibited the CaV2.2-CRMP2 interaction in a concentration-dependent fashion and diminished surface expression of CaV2.2 and depolarization-evoked Ca influx in rat dorsal root ganglia neurons. In vitro studies demonstrated suppression of excitability of small-to-medium diameter dorsal root ganglion and inhibition of subtypes of voltage-gated Ca channels. Sprague-Dawley rats with tibial nerve injury had profound and long-lasting tactile allodynia and ongoing pain. Immediate administration of R9-CBD3-A6K produced enhanced dopamine release from the nucleus accumbens shell selectively in injured animals, consistent with relief of ongoing pain. R9-CBD3-A6K, when administered repeatedly into the central nervous system ventricles of naive rats, did not result in a positive conditioned place preference demonstrating a lack of abusive liability. Continuous subcutaneous infusion of R9-CBD3-A6K over a 24- to 72-hour period reversed tactile allodynia and ongoing pain, demonstrating a lack of tolerance over this time course. Importantly, continuous infusion of R9-CBD3-A6K did not affect motor activity, anxiety, depression, or memory and learning. Collectively, these results validate the potential therapeutic significance of targeting the CaV-CRMP2 axis for treatment of neuropathic pain.
authors.affiliation: Departments of Pharmacology.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Xie
authors.affiliation: Departments of Pharmacology.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Chew
authors.affiliation: Departments of Pharmacology.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Yang
authors.affiliation: Departments of Pharmacology.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Pharmacology.
authors.forename: Chaoling
authors.initials: C
authors.lastname: Qu
authors.affiliation: Departments of Pharmacology.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Anatomy and Cell Biology and.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Federici
authors.affiliation: Anatomy and Cell Biology and.
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Fitz
authors.affiliation: Departments of Anesthesia.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Ripsch
authors.affiliation: Departments of Anesthesia.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Due
authors.affiliation: Departments of Pharmacology.
authors.forename: Aubin
authors.initials: A
authors.lastname: Moutal
authors.affiliation: Departments of Pharmacology.
authors.forename: May
authors.initials: M
authors.lastname: Khanna
authors.affiliation: Departments of Anesthesia.|Anatomy and Cell Biology and.
authors.forename: Fletcher A
authors.initials: FA
authors.lastname: White
authors.affiliation: Departments of Pharmacology.|Neurology and.|Anesthesiology, Tucson, AZ, USA.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.affiliation: Anatomy and Cell Biology and.|Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Johnson
authors.affiliation: Departments of Pharmacology.|Anesthesiology, Tucson, AZ, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.affiliation: Departments of Pharmacology.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000209:etiology; D052158:Aptamers, Peptide / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004558:Electric Stimulation; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D019417:Hindlimb Suspension; D006930:Hyperalgesia / Q000188:drug therapy; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry*; D018782:Maze Learning / Q000187:drug effects; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D009437:Neuralgia / Q000188:drug therapy* / Q000473:pathology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects
chemical_list: D052158:Aptamers, Peptide; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C095114:collapsin response mediator protein-2; D004298:Dopamine