Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Medicine volume 17, pages 822–829 (2011)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A CRMP-2 peptide suppresses the interaction between CaV2.2 and CRMP-2.
Figure 2: TAT-CBD3 reduces Ca2+ currents in DRGs and excitatory synaptic transmission in lamina II neurons from spinal cord slices.
Figure 3: TAT-CBD3 reduces capsaicin-stimulated release of iCGRP from spinal cord slices.
Figure 4: TAT-CBD3 reduces changes in meningeal blood flow induced by capsaicin.
Figure 5: TAT-CBD3 reduces acute, inflammatory and neuropathic pain.
Figure 6: TAT-CBD3 has no effect on sensorimotor and cognitive functions but has a mild anxiolytic effect.

Similar content being viewed by others

References

  1. Staats, P.S. et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. J. Am. Med. Assoc. 291, 63–70 (2004).

    Article  CAS  Google Scholar 

  2. Rauck, R.L. et al. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J. Pain Symptom Manage. 31, 393–406 (2006).

    Article  CAS  Google Scholar 

  3. Wallace, M.S. Intrathecal ziconotide for severe chronic pain: safety and tolerability results of an open-label, long-term trial. Anesth. Analg. 106, 628–637 (2008).

    Article  CAS  Google Scholar 

  4. Schmidtko, A., Lotsch, J., Freynhagen, R. & Geisslinger, G. Ziconotide for treatment of severe chronic pain. Lancet 375, 1569–1577 (2010).

    Article  CAS  Google Scholar 

  5. Brittain, J.M. et al. An atypical role for collapsin response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltage-gated Ca2+ channels. J. Biol. Chem. 284, 31375–31390 (2009).

    Article  CAS  Google Scholar 

  6. Chi, X.X. et al. Regulation of N-type voltage-gated calcium (CaV2.2) channels and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons. J. Cell Sci. 122, 4351–4362 (2009).

    Article  CAS  Google Scholar 

  7. Goshima, Y., Nakamura, F., Strittmatter, P. & Strittmatter, S.M. Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature 376, 509–514 (1995).

    Article  CAS  Google Scholar 

  8. Inagaki, N. et al. CRMP-2 induces axons in cultured hippocampal neurons. Nat. Neurosci. 4, 781–782 (2001).

    Article  CAS  Google Scholar 

  9. Yoshimura, T. et al. GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120, 137–149 (2005).

    Article  CAS  Google Scholar 

  10. Morita, T. & Sobue, K. Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway. J. Biol. Chem. 284, 27734–27745 (2009).

    Article  CAS  Google Scholar 

  11. Arimura, N. et al. CRMP-2 directly binds to cytoplasmic dynein and interferes with its activity. J. Neurochem. 111, 380–390 (2009).

    Article  CAS  Google Scholar 

  12. Fukata, Y. et al. CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat. Cell Biol. 4, 583–591 (2002).

    Article  CAS  Google Scholar 

  13. Wang, Y. et al. In silico docking and electrophysiological characterization of lacosamide binding sites on collapsin response mediator protein 2 (CRMP-2) identifies a pocket important in modulating sodium channel slow inactivation. J. Biol. Chem. 285, 25296–25307 (2010).

    Article  CAS  Google Scholar 

  14. Schwarze, S.R., Ho, A., Vocero-Akbani, A. & Dowdy, S.F. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285, 1569–1572 (1999).

    Article  CAS  Google Scholar 

  15. Andrade, A., Denome, S., Jiang, Y.Q., Marangoudakis, S. & Lipscombe, D. Opioid inhibition of N-type Ca2+ channels and spinal analgesia couple to alternative splicing. Nat. Neurosci. 13, 1249–1256 (2010).

    Article  CAS  Google Scholar 

  16. Todd, A.J. Neuronal circuitry for pain processing in the dorsal horn. Nat. Rev. Neurosci. 11, 823–836 (2010).

    Article  CAS  Google Scholar 

  17. Liu, T., Xu, Z.Z., Park, C.K., Berta, T. & Ji, R.R. Toll-like receptor 7 mediates pruritus. Nat. Neurosci. 13, 1460–1462 (2010).

    Article  CAS  Google Scholar 

  18. Yamamoto, T. & Takahara, A. Recent updates of N-type calcium channel blockers with therapeutic potential for neuropathic pain and stroke. Curr. Top. Med. Chem. 9, 377–395 (2009).

    Article  CAS  Google Scholar 

  19. Zamponi, G.W., Lewis, R.J., Todorovic, S.M., Arneric, S.P. & Snutch, T.P. Role of voltage-gated calcium channels in ascending pain pathways. Brain Res. Rev. 60, 84–89 (2009).

    Article  CAS  Google Scholar 

  20. Catterall, W.A. & Few, A.P. Calcium channel regulation and presynaptic plasticity. Neuron 59, 882–901 (2008).

    Article  CAS  Google Scholar 

  21. Dodge, F.A. Jr. & Rahamimoff, R. Co-operative action a calcium ions in transmitter release at the neuromuscular junction. J. Physiol. (Lond.) 193, 419–432 (1967).

    Article  CAS  Google Scholar 

  22. Patapoutian, A., Tate, S. & Woolf, C.J. Transient receptor potential channels: targeting pain at the source. Nat. Rev. Drug Discov. 8, 55–68 (2009).

    Article  CAS  Google Scholar 

  23. Goadsby, P.J. Calcitonin gene-related peptide (CGRP) antagonists and migraine: is this a new era? Neurology 70, 1300–1301 (2008).

    Article  Google Scholar 

  24. Kunkler, P.E., Ballard, C.J., Oxford, G.S. & Hurley, J.H. TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation. Pain 152, 38–44 (2010).

    Article  Google Scholar 

  25. Snutch, T.P. Targeting chronic and neuropathic pain: the N-type calcium channel comes of age. NeuroRx 2, 662–670 (2005).

    Article  Google Scholar 

  26. Dubuisson, D. & Dennis, S.G. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 4, 161–174 (1977).

    Article  CAS  Google Scholar 

  27. Hunskaar, S. & Hole, K. The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain 30, 103–114 (1987).

    Article  CAS  Google Scholar 

  28. Dickenson, A.H. & Sullivan, A.F. Subcutaneous formalin-induced activity of dorsal horn neurones in the rat: differential response to an intrathecal opiate administered pre or post formalin. Pain 30, 349–360 (1987).

    Article  CAS  Google Scholar 

  29. Coderre, T.J., Vaccarino, A.L. & Melzack, R. Central nervous system plasticity in the tonic pain response to subcutaneous formalin injection. Brain Res. 535, 155–158 (1990).

    Article  CAS  Google Scholar 

  30. Guo, A., Vulchanova, L., Wang, J., Li, X. & Elde, R. Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur. J. Neurosci. 11, 946–958 (1999).

    Article  CAS  Google Scholar 

  31. Nakamura, A. et al. Morphological and immunohistochemical characterization of the trigeminal ganglion neurons innervating the cornea and upper eyelid of the rat. J. Chem. Neuroanat. 34, 95–101 (2007).

    Article  Google Scholar 

  32. Joseph, E.K., Chen, X., Khasar, S.G. & Levine, J.D. Novel mechanism of enhanced nociception in a model of AIDS therapy-induced painful peripheral neuropathy in the rat. Pain 107, 147–158 (2004).

    Article  Google Scholar 

  33. Bhangoo, S.K., Ripsch, M.S., Buchanan, D.J., Miller, R.J. & White, F.A. Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy. Mol. Pain. 5, 48 (2009).

    Article  Google Scholar 

  34. Cai, S.R. et al. The kinetics and tissue distribution of protein transduction in mice. Eur. J. Pharm. Sci. 27, 311–319 (2006).

    Article  CAS  Google Scholar 

  35. Hamm, R.J., Pike, B.R., O'Dell, D.M., Lyeth, B.G. & Jenkins, L.W. The rotarod test: an evaluation of its effectiveness in assessing motor deficits following traumatic brain injury. J. Neurotrauma 11, 187–196 (1994).

    Article  CAS  Google Scholar 

  36. D'Hooge, R. & De Deyn, P.P. Applications of the Morris water maze in the study of learning and memory. Brain Res. Brain Res. Rev. 36, 60–90 (2001).

    Article  CAS  Google Scholar 

  37. Gage, F.H., Chen, K.S., Buzsaki, G. & Armstrong, D. Experimental approaches to age-related cognitive impairments. Neurobiol. Aging 9, 645–655 (1988).

    Article  CAS  Google Scholar 

  38. Rauck, R.L., Wallace, M.S., Burton, A.W., Kapural, L. & North, J.M. Intrathecal ziconotide for neuropathic pain: a review. Pain Pract. 9, 327–337 (2009).

    Article  Google Scholar 

  39. Bourin, M. & Hascoet, M. The mouse light/dark box test. Eur. J. Pharmacol. 463, 55–65 (2003).

    Article  CAS  Google Scholar 

  40. Lalonde, R. & Strazielle, C. Relations between open-field, elevated plus-maze, and emergence tests as displayed by C57/BL6J and BALB/c mice. J. Neurosci. Methods 171, 48–52 (2008).

    Article  CAS  Google Scholar 

  41. Varty, G.B., Cohen-Williams, M.E. & Hunter, J.C. The antidepressant-like effects of neurokinin NK1 receptor antagonists in a gerbil tail suspension test. Behav. Pharmacol. 14, 87–95 (2003).

    Article  CAS  Google Scholar 

  42. Cryan, J.F., Mombereau, C. & Vassout, A. The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci. Biobehav. Rev. 29, 571–625 (2005).

    Article  CAS  Google Scholar 

  43. Schwarze, S.R. & Dowdy, S.F. In vivo protein transduction: intracellular delivery of biologically active proteins, compounds and DNA. Trends Pharmacol. Sci. 21, 45–48 (2000).

    Article  CAS  Google Scholar 

  44. Yoon, J.S. et al. Characteristics of HIV-Tat protein transduction domain. J. Microbiol. 42, 328–335 (2004).

    CAS  PubMed  Google Scholar 

  45. Winquist, R.J., Pan, J.Q. & Gribkoff, V.K. Use-dependent blockade of Cav2.2 voltage-gated calcium channels for neuropathic pain. Biochem. Pharmacol. 70, 489–499 (2005).

    Article  CAS  Google Scholar 

  46. Cizkova, D. et al. Localization of N-type Ca2+ channels in the rat spinal cord following chronic constrictive nerve injury. Exp. Brain Res. 147, 456–463 (2002).

    Article  CAS  Google Scholar 

  47. Saegusa, H. et al. Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca2+ channel. EMBO J. 20, 2349–2356 (2001).

    Article  CAS  Google Scholar 

  48. Malmberg, A.B. & Yaksh, T.L. Voltage-sensitive calcium channels in spinal nociceptive processing: blockade of N- and P-type channels inhibits formalin-induced nociception. J. Neurosci. 14, 4882–4890 (1994).

    Article  CAS  Google Scholar 

  49. Seward, E., Hammond, C. & Henderson, G. Mu-opioid-receptor-mediated inhibition of the N-type calcium-channel current. Proc. Biol. Soc. 244, 129–135 (1991).

    Article  CAS  Google Scholar 

  50. Bell, T.J., Thaler, C., Castiglioni, A.J., Helton, T.D. & Lipscombe, D. Cell-specific alternative splicing increases calcium channel current density in the pain pathway. Neuron 41, 127–138 (2004).

    Article  CAS  Google Scholar 

  51. Altier, C. et al. Differential role of N-type calcium channel splice isoforms in pain. J. Neurosci. 27, 6363–6373 (2007).

    Article  CAS  Google Scholar 

  52. Farazifard, R., Safarpour, F., Sheibani, V. & Javan, M. Eye-wiping test: a sensitive animal model for acute trigeminal pain studies. Brain Res. Brain Res. Protoc. 16, 44–49 (2005).

    Article  Google Scholar 

  53. Le Bars, D., Gozariu, M. & Cadden, S.W. Animal models of nociception. Pharmacol. Rev. 53, 597–652 (2001).

    CAS  PubMed  Google Scholar 

  54. Doak, G.J. & Sawynok, J. Formalin-induced nociceptive behavior and edema: involvement of multiple peripheral 5-hydroxytryptamine receptor subtypes. Neuroscience 80, 939–949 (1997).

    Article  CAS  Google Scholar 

  55. Whiteside, G.T., Boulet, J.M. & Walker, K. The role of central and peripheral mu opioid receptors in inflammatory pain and edema: a study using morphine and DiPOA ([8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl]-acetic acid). J. Pharmacol. Exp. Ther. 314, 1234–1240 (2005).

    Article  CAS  Google Scholar 

  56. Yarchoan, R. et al. Phase 1 studies of 2′,3′-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet 1, 76–81 (1988).

    Article  CAS  Google Scholar 

  57. Dubinsky, R.M., Yarchoan, R., Dalakas, M. & Broder, S. Reversible axonal neuropathy from the treatment of AIDS and related disorders with 2′,3′-dideoxycytidine (ddC). Muscle Nerve 12, 856–860 (1989).

    Article  CAS  Google Scholar 

  58. Bhangoo, S.K. et al. CXCR4 chemokine receptor signaling mediates pain hypersensitivity in association with antiretroviral toxic neuropathy. Brain Behav. Immun. 21, 581–591 (2007).

    Article  CAS  Google Scholar 

  59. Nakanishi, O., Ishikawa, T. & Imamura, Y. Modulation of formalin-evoked hyperalgesia by 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

  1. Joel M Brittain and Djane B Duarte: These authors contributed equally to this work.

Authors and Affiliations

  1. 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

  2. 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

  3. 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

  4. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Philip L Johnson, Stephanie D Fitz & Anantha Shekhar

  5. Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Naikui Liu

  6. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Wenhui Xiong, Xiaoming Jin & Xiao-Ming Xu

  7. 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

  8. 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

  9. Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Cynthia M Hingtgen & Xiao-Ming Xu

  10. Department of Indiana Clinical and Translational Sciences Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Anantha Shekhar

Authors
  1. Joel M Brittain
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Djane B Duarte
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sarah M Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weiguo Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carrie Ballard
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Philip L Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Naikui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wenhui Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Matthew S Ripsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yuying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jill C Fehrenbacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Stephanie D Fitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. May Khanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Chul-Kyu Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Brian S Schmutzler
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Bo Myung Cheon
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Michael R Due
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Tatiana Brustovetsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Nicole M Ashpole
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Andy Hudmon
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Samy O Meroueh
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Cynthia M Hingtgen
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Nickolay Brustovetsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Ru-Rong Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Joyce H Hurley
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Xiaoming Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Anantha Shekhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Xiao-Ming Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Gerry S Oxford
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Michael R Vasko
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Fletcher A White
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Rajesh Khanna
    View author publications

    You can also search for this author in PubMed 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:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2345

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing