Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca2+ channel complex

Joel M. Brittain, Djane B. Duarte, Sarah M. Wilson, Weiguo Zhu, Carrie Ballard, Philip Johnson, Naikui Liu, Wenhui Xiong, Matthew S. Ripsch, Yuying Wang, Jill Fehrenbacher, Stephanie D. Fitz, May Khanna, Chul Kyu Park, Brian S. Schmutzler, Bo Myung Cheon, Michael R. Due, Tatiana Brustovetsky, Nicole M. Ashpole, Andy HudmonSamy Meroueh, Cynthia M. Hingtgen, Nikolai Broustovetski, Ru Rong Ji, Joyce Hurley, Xiaoming Jin, Anantha Shekhar, Xiao-Ming Xu, Gerry S. Oxford, Michael Vasko, Fletcher White, Rajesh Khanna

Research output: Contribution to journalArticle

116 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)822-829
Number of pages8
JournalNature Medicine
Volume17
Issue number7
DOIs
StatePublished - Jul 2011

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Trans-Activators
Neuralgia
Transcription
Hypersensitivity
Human Immunodeficiency Virus rev Gene Products
Neurons
Posterior Horn Cells
Capsaicin
Anti-Anxiety Agents
Calcium Channel Blockers
Sensory Receptor Cells
Neuropeptides
Synaptic Transmission
Chronic Pain
Formaldehyde
Calcium Channels
Depression
Pain
Blood
Peptides

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca2+ channel complex. / Brittain, Joel M.; Duarte, Djane B.; Wilson, Sarah M.; Zhu, Weiguo; Ballard, Carrie; Johnson, Philip; Liu, Naikui; Xiong, Wenhui; Ripsch, Matthew S.; Wang, Yuying; Fehrenbacher, Jill; Fitz, Stephanie D.; Khanna, May; Park, Chul Kyu; Schmutzler, Brian S.; Cheon, Bo Myung; Due, Michael R.; Brustovetsky, Tatiana; Ashpole, Nicole M.; Hudmon, Andy; Meroueh, Samy; Hingtgen, Cynthia M.; Broustovetski, Nikolai; Ji, Ru Rong; Hurley, Joyce; Jin, Xiaoming; Shekhar, Anantha; Xu, Xiao-Ming; Oxford, Gerry S.; Vasko, Michael; White, Fletcher; Khanna, Rajesh.

In: Nature Medicine, Vol. 17, No. 7, 07.2011, p. 822-829.

Research output: Contribution to journalArticle

Brittain, JM, Duarte, DB, Wilson, SM, Zhu, W, Ballard, C, Johnson, P, Liu, N, Xiong, W, Ripsch, MS, Wang, Y, Fehrenbacher, J, Fitz, SD, Khanna, M, Park, CK, Schmutzler, BS, Cheon, BM, Due, MR, Brustovetsky, T, Ashpole, NM, Hudmon, A, Meroueh, S, Hingtgen, CM, Broustovetski, N, Ji, RR, Hurley, J, Jin, X, Shekhar, A, Xu, X-M, Oxford, GS, Vasko, M, White, F & Khanna, R 2011, 'Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca2+ channel complex', Nature Medicine, vol. 17, no. 7, pp. 822-829. https://doi.org/10.1038/nm.2345
Brittain, Joel M. ; Duarte, Djane B. ; Wilson, Sarah M. ; Zhu, Weiguo ; Ballard, Carrie ; Johnson, Philip ; Liu, Naikui ; Xiong, Wenhui ; Ripsch, Matthew S. ; Wang, Yuying ; Fehrenbacher, Jill ; Fitz, Stephanie D. ; Khanna, May ; Park, Chul Kyu ; Schmutzler, Brian S. ; Cheon, Bo Myung ; Due, Michael R. ; Brustovetsky, Tatiana ; Ashpole, Nicole M. ; Hudmon, Andy ; Meroueh, Samy ; Hingtgen, Cynthia M. ; Broustovetski, Nikolai ; Ji, Ru Rong ; Hurley, Joyce ; Jin, Xiaoming ; Shekhar, Anantha ; Xu, Xiao-Ming ; Oxford, Gerry S. ; Vasko, Michael ; White, Fletcher ; Khanna, Rajesh. / Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca2+ channel complex. In: Nature Medicine. 2011 ; Vol. 17, No. 7. pp. 822-829.
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