title: Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca²⁺ channel complex.
abstract: The use of N-type voltage-gated calcium channel (CaV2.2) blockers to treat pain is limited by many physiological side effects. Here we report that inflammatory and neuropathic hypersensitivity can be suppressed by inhibiting the binding of collapsin response mediator protein 2 (CRMP-2) to CaV2.2 and thereby reducing channel function. A peptide of CRMP-2 fused to the HIV transactivator of transcription (TAT) protein (TAT-CBD3) decreased neuropeptide release from sensory neurons and excitatory synaptic transmission in dorsal horn neurons, reduced meningeal blood flow, reduced nocifensive behavior induced by formalin injection or corneal capsaicin application and reversed neuropathic hypersensitivity produced by an antiretroviral drug. TAT-CBD3 was mildly anxiolytic without affecting memory retrieval, sensorimotor function or depression. At doses tenfold higher than that required to reduce hypersensitivity in vivo, TAT-CBD3 caused a transient episode of tail kinking and body contortion. By preventing CRMP-2-mediated enhancement of CaV2.2 function, TAT-CBD3 alleviated inflammatory and neuropathic hypersensitivity, an approach that may prove useful in managing chronic pain.
authors.affiliation: Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Brittain
authors.forename: Djane B
authors.initials: DB
authors.lastname: Duarte
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Wilson
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhu
authors.forename: Carrie
authors.initials: C
authors.lastname: Ballard
authors.forename: Philip L
authors.initials: PL
authors.lastname: Johnson
authors.forename: Naikui
authors.initials: N
authors.lastname: Liu
authors.forename: Wenhui
authors.initials: W
authors.lastname: Xiong
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Ripsch
authors.forename: Yuying
authors.initials: Y
authors.lastname: Wang
authors.forename: Jill C
authors.initials: JC
authors.lastname: Fehrenbacher
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Fitz
authors.forename: May
authors.initials: M
authors.lastname: Khanna
authors.forename: Chul-Kyu
authors.initials: CK
authors.lastname: Park
authors.forename: Brian S
authors.initials: BS
authors.lastname: Schmutzler
authors.forename: Bo Myung
authors.initials: BM
authors.lastname: Cheon
authors.forename: Michael R
authors.initials: MR
authors.lastname: Due
authors.forename: Tatiana
authors.initials: T
authors.lastname: Brustovetsky
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Ashpole
authors.forename: Andy
authors.initials: A
authors.lastname: Hudmon
authors.forename: Samy O
authors.initials: SO
authors.lastname: Meroueh
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Hingtgen
authors.forename: Nickolay
authors.initials: N
authors.lastname: Brustovetsky
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.forename: Joyce H
authors.initials: JH
authors.lastname: Hurley
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Jin
authors.forename: Anantha
authors.initials: A
authors.lastname: Shekhar
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Xu
authors.forename: Gerry S
authors.initials: GS
authors.lastname: Oxford
authors.forename: Michael R
authors.initials: MR
authors.lastname: Vasko
authors.forename: Fletcher A
authors.initials: FA
authors.lastname: White
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004388:Dura Mater / Q000187:drug effects / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010446:Peptide Fragments / Q000187:drug effects / Q000502:physiology*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects
chemical_list: C000590315:CBD3 peptide; C503279:Cacna1b protein, rat; D020864:Calcium Channels, N-Type; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C095114:collapsin response mediator protein-2