Suppression of inflammatory and neuropathic pain by uncoupling crmp-2 from the presynaptic ca2+ channel complex

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Suppression of inflammatory and neuropathic pain by uncoupling crmp-2 from the presynaptic ca2+ channel complex"


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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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intrathecal N-type Ca channel and protein kinase C inhibitor in the rat. _Cell. Mol. Neurobiol._ 19, 191–197 (1999). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS This


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


publications You can also search for this author inPubMed Google Scholar * Djane B Duarte View author publications You can also search for this author inPubMed Google Scholar * Sarah M


Wilson View author publications You can also search for this author inPubMed Google Scholar * Weiguo Zhu View author publications You can also search for this author inPubMed Google Scholar


* Carrie Ballard View author publications You can also search for this author inPubMed Google Scholar * Philip L Johnson View author publications You can also search for this author inPubMed


 Google Scholar * Naikui Liu View author publications You can also search for this author inPubMed Google Scholar * Wenhui Xiong View author publications You can also search for this author


inPubMed Google Scholar * Matthew S Ripsch View author publications You can also search for this author inPubMed Google Scholar * Yuying Wang View author publications You can also search for


this author inPubMed Google Scholar * Jill C Fehrenbacher View author publications You can also search for this author inPubMed Google Scholar * Stephanie D Fitz View author publications


You can also search for this author inPubMed Google Scholar * May Khanna View author publications You can also search for this author inPubMed Google Scholar * Chul-Kyu Park View author


publications You can also search for this author inPubMed Google Scholar * Brian S Schmutzler View author publications You can also search for this author inPubMed Google Scholar * Bo Myung


Cheon View author publications You can also search for this author inPubMed Google Scholar * Michael R Due View author publications You can also search for this author inPubMed Google


Scholar * Tatiana Brustovetsky View author publications You can also search for this author inPubMed Google Scholar * Nicole M Ashpole View author publications You can also search for this


author inPubMed Google Scholar * Andy Hudmon View author publications You can also search for this author inPubMed Google Scholar * Samy O Meroueh View author publications You can also


search for this author inPubMed Google Scholar * Cynthia M Hingtgen View author publications You can also search for this author inPubMed Google Scholar * Nickolay Brustovetsky View author


publications You can also search for this author inPubMed Google Scholar * Ru-Rong Ji View author publications You can also search for this author inPubMed Google Scholar * Joyce H Hurley


View author publications You can also search for this author inPubMed Google Scholar * Xiaoming Jin View author publications You can also search for this author inPubMed Google Scholar *


Anantha Shekhar View author publications You can also search for this author inPubMed Google Scholar * Xiao-Ming Xu View author publications You can also search for this author inPubMed 


Google Scholar * Gerry S Oxford View author publications You can also search for this author inPubMed Google Scholar * Michael R Vasko View author publications You can also search for this


author inPubMed Google Scholar * Fletcher A White View author publications You can also search for this author inPubMed Google Scholar * Rajesh Khanna View author publications You can also


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 *


Published: 05 June 2011 * Issue Date: July 2011 * DOI: https://doi.org/10.1038/nm.2345 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get


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