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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

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* Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS INHIBITING HV1 CHANNEL IN PERIPHERAL SENSORY NEURONS ATTENUATES

CHRONIC INFLAMMATORY PAIN AND OPIOID SIDE EFFECTS Article 03 February 2022 GLP-1 AND ITS DERIVED PEPTIDES MEDIATE PAIN RELIEF THROUGH DIRECT TRPV1 INHIBITION WITHOUT AFFECTING

THERMOREGULATION Article Open access 01 November 2024 INHIBITING ENDOCYTOSIS IN CGRP+ NOCICEPTORS ATTENUATES INFLAMMATORY PAIN-LIKE BEHAVIOR Article Open access 04 October 2021 REFERENCES *

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work is supported by grants from the US National Institutes of Health: Dental and Craniofacial Research (DE14318-06 to J.C.F. and DE017794 to R.-R.J.), Drug Abuse (DA026040 to F.A.W.),

Neurological Disorders and Stroke (NS051668 to C.M.H. and NS050131 to N.B.) and Environmental Health Sciences (ES017430 to G.S.O. and J.H.H.); the Indiana State Department of Health−Spinal

Cord and Brain Injury Fund (A70-0-079212 to N.B. and A70-9-079138 to R.K.) and the Indiana University Biomedical Committee–Research Support Funds (2286501 to R.K.); a National Scientist

Development Grant from the American Heart Association (SDG5280023 to R.K.); and the Elwert Award in Medicine to R.K. J.M.B. is the recipient of a Larry Kays Medical Neuroscience fellowship.

S.M.W. is a Stark Scholar. We thank A. Molosh and members of the Pain and Sensory Group for discussions, S.K. Ahuja for assistance with behavioral experiments and C. Kohn for comments on the

manuscript. AUTHOR INFORMATION Author notes * Joel M Brittain and Djane B Duarte: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Program in Medical

Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA Joel M Brittain, Djane B Duarte, Sarah M Wilson, 

Weiguo Zhu, Carrie Ballard, Naikui Liu, Wenhui Xiong, Matthew S Ripsch, Yuying Wang, Jill C Fehrenbacher, Brian S Schmutzler, Bo Myung Cheon, Michael R Due, Nicole M Ashpole, Andy Hudmon, 

Samy O Meroueh, Cynthia M Hingtgen, Nickolay Brustovetsky, Joyce H Hurley, Xiaoming Jin, Xiao-Ming Xu, Gerry S Oxford, Michael R Vasko, Fletcher A White & Rajesh Khanna * Department of

Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA Weiguo Zhu, Yuying Wang, Jill C Fehrenbacher, Brian S Schmutzler, Tatiana Brustovetsky, Andy

Hudmon, Cynthia M Hingtgen, Nickolay Brustovetsky, Gerry S Oxford, Michael R Vasko & Rajesh Khanna * Department of Biochemistry and Molecular Biology, Indiana University School of

Medicine, Indianapolis, Indiana, USA Carrie Ballard, May Khanna, Nicole M Ashpole, Andy Hudmon, Samy O Meroueh & Joyce H Hurley * Department of Psychiatry, Indiana University School of

Medicine, Indianapolis, Indiana, USA Philip L Johnson, Stephanie D Fitz & Anantha Shekhar * Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis,

Indiana, USA Naikui Liu * Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA Wenhui Xiong, Xiaoming Jin & Xiao-Ming Xu * Department

of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana, USA Matthew S Ripsch, Jill C Fehrenbacher, Bo Myung Cheon, Michael R Due, Michael R Vasko & Fletcher A White

* Department of Anesthesiology, Sensory Plasticity Laboratory, Pain Research Center, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston,

Massachusetts, USA Chul-Kyu Park & Ru-Rong Ji * Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA Cynthia M Hingtgen & Xiao-Ming Xu *

Department of Indiana Clinical and Translational Sciences Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA Anantha Shekhar Authors * Joel M Brittain View author

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search for this author inPubMed Google Scholar CONTRIBUTIONS J.M.B. performed molecular biology, biochemistry and calcium imaging experiments and analyzed the data. D.B.D. carried out the

spinal cord slice release and formalin behavior experiments and helped to write the manuscript. S.M.W. performed immunocytochemistry and wrote the manuscript. C.B. carried out the laser

Doppler blood flowmetry. J.H.H. analyzed the blood flow data. P.L.J. and S.D.F. performed anxiety and despair behavior experiments. W.Z. and Y.W. performed DRG and hippocampal patching.

C.-K.P. conducted electrophysiology in spinal cord slices. W.X. and X.J. performed electrophysiology on brain slices. B.S.S. carried out the DRG release assays. T.B., N.B. and J.M.B.

performed and analyzed the calcium imaging experiments. B.M.C., M.R.D. and M.S.R. performed DRG immunocytochemistry and ddC behavior experiments. M.K. and S.O.M. performed the surface

plasmon resonance experiments and analyzed the data. N.L. performed the rotarod and water maze experiments. J.C.F. performed the nocifensive behavior experiments and editing of the

manuscript. N.M.A. and A.H. synthesized the peptide blot. X.-M.X., C.M.H., M.R.V., G.S.O. and A.S. contributed to editing of the manuscript. R.-R.J contributed to electrophysiology of spinal

cord slices and editing of the manuscript. F.A.W. analyzed the ddC behavior data and contributed to writing and editing the manuscript. R.K. identified the peptide, conceived the study,

designed and supervised the overall project and wrote the manuscript. CORRESPONDING AUTHOR Correspondence to Rajesh Khanna. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no

competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Figures 1–7, Supplementary Table 1 and Supplementary Methods (PDF 2807 kb) RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Brittain, J., Duarte, D., Wilson, S. _et al._ Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2

from the presynaptic Ca2+ channel complex. _Nat Med_ 17, 822–829 (2011). https://doi.org/10.1038/nm.2345 Download citation * Received: 14 September 2010 * Accepted: 07 March 2011 *

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