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.

AAV-encoded CaV2.2 peptide aptamer CBD3A6K for primary sensory neuron-targeted treatment of established neuropathic pain

Gene Therapy volume 26, pages 308–323 (2019)Cite this article

Subjects

Abstract

Transmission of pain signals from primary sensory neurons to secondary neurons of the central nervous system is critically dependent on presynaptic voltage-gated calcium channels. Calcium channel-binding domain 3 (CBD3), derived from the collapsin response mediator protein 2 (CRMP2), is a peptide aptamer that is effective in blocking N-type voltage-gated calcium channel (CaV2.2) activity. We previously reported that recombinant adeno-associated virus (AAV)-mediated restricted expression of CBD3 affixed to enhanced green fluorescent protein (EGFP) in primary sensory neurons prevents the development of cutaneous mechanical hypersensitivity in a rat neuropathic pain model. In this study, we tested whether this strategy is effective in treating established pain. We constructed AAV6-EGFP-CBD3A6K (AAV6-CBD3A6K) expressing a fluorescent CBD3A6K (replacing A to K at position 6 of CBD3 peptide), which is an optimized variant of the parental CBD3 peptide that is a more potent blocker of CaV2.2. Delivery of AAV6-CBD3A6K into lumbar (L) 4 and 5 dorsal root ganglia (DRG) of rats 2 weeks following tibial nerve injury (TNI) induced transgene expression in neurons of these DRG and their axonal projections, accompanied by attenuation of pain behavior. We additionally observed that the increased CaV2.2α1b immunoreactivity in the ipsilateral spinal cord dorsal horn and DRG following TNI was significantly normalized by AAV6-CBD3A6K treatment. Finally, the increased neuronal activity in the ipsilateral dorsal horn that developed after TNI was reduced by AAV6-CBD3A6K treatment. Collectively, these results indicate that DRG-restricted AAV6 delivery of CBD3A6K is an effective analgesic molecular strategy for the treatment of established neuropathic pain.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. Dzau VJ, Pizzo PA. Relieving pain in America: insights from an Institute of Medicine committee. JAMA. 2014;312:1507–8. https://doi.org/10.1001/jama.2014.12986

    Article  CAS  PubMed  Google Scholar 

  2. Loeser JD. Relieving pain in America. Clin J Pain. 2012;28:185–6. https://doi.org/10.1097/AJP.0b013e318230f6c1

    Article  PubMed  Google Scholar 

  3. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139:267–84. https://doi.org/10.1016/j.cell.2009.09.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1–32. https://doi.org/10.1146/annurev.neuro.051508.135531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron. 2006;52:77–92. https://doi.org/10.1016/j.neuron.2006.09.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bucci G, Mochida S, Stephens GJ. Inhibition of synaptic transmission and G protein modulation by synthetic CaV2.2 Ca(2)+ channel peptides. J Physiol. 2011;589:3085–101. https://doi.org/10.1113/jphysiol.2010.204735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bell TJ, Thaler C, Castiglioni AJ, Helton TD, Lipscombe D. Cell-specific alternative splicing increases calcium channel current density in the pain pathway. Neuron. 2004;41:127–38.

    Article  CAS  Google Scholar 

  8. Altier C, Dale CS, Kisilevsky AE, Chapman K, Castiglioni AJ, Matthews EA, et al. Differential role of N-type calcium channel splice isoforms in pain. J Neurosci. 2007;27:6363–73. https://doi.org/10.1523/JNEUROSCI.0307-07.2007

    Article  CAS  PubMed  Google Scholar 

  9. Bauer CS, Nieto-Rostro M, Rahman W, Tran-Van-Minh A, Ferron L, Douglas L, et al. The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. J Neurosci. 2009;29:4076–88. https://doi.org/10.1523/JNEUROSCI.0356-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ji RR, Strichartz G. Cell signaling and the genesis of neuropathic pain. Sci STKE. 2004;2004:reE14 https://doi.org/10.1126/stke.2522004re14

    Article  PubMed  Google Scholar 

  11. Tyagarajan S, Chakravarty PK, Park M, Zhou B, Herrington JB, Ratliff K, et al. A potent and selective indole N-type calcium channel (Ca(v)2.2) blocker for the treatment of pain. Bioorg Med Chem Lett. 2011;21:869–73. https://doi.org/10.1016/j.bmcl.2010.11.067

    Article  CAS  PubMed  Google Scholar 

  12. Liang M, Yin XL, Shi HB, Li CY, Li XY, Song NY, et al. Bilirubin augments Ca(2+) load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels. Sci Rep. 2017;7:431 https://doi.org/10.1038/s41598-017-00275-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Norton RS, McDonough SI. Peptides targeting voltage-gated calcium channels. Curr Pharm Des. 2008;14:2480–91.

    Article  CAS  Google Scholar 

  14. Perret D, Luo ZD. Targeting voltage-gated calcium channels for neuropathic pain management. Neurotherapeutics. 2009;6:679–92. https://doi.org/10.1016/j.nurt.2009.07.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pexton T, Moeller-Bertram T, Schilling JM, Wallace MS. Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development. Expert Opin Investig Drugs. 2011;20:1277–84. https://doi.org/10.1517/13543784.2011.600686

    Article  CAS  PubMed  Google Scholar 

  16. Vink S, Alewood PF. Targeting voltage-gated calcium channels: developments in peptide and small-molecule inhibitors for the treatment of neuropathic pain. Br J Pharmacol. 2012;167:970–89. https://doi.org/10.1111/j.1476-5381.2012.02082.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zamponi GW. Targeting voltage-gated calcium channels in neurological and psychiatric diseases. Nat Rev Drug Discov. 2016;15:19–34. https://doi.org/10.1038/nrd.2015.5

    Article  CAS  PubMed  Google Scholar 

  18. Park J, Luo ZD. Calcium channel functions in pain processing. Channels. 2010;4:510–7.

    Article  CAS  Google Scholar 

  19. Patel R, Montagut-Bordas C, Dickenson AH. Calcium channel modulation as a target in chronic pain control. Br J Pharmacol. 2018;175:2173–84. https://doi.org/10.1111/bph.13789

    Article  CAS  PubMed  Google Scholar 

  20. McGivern JG. Targeting N-type and T-type calcium channels for the treatment of pain. Drug Discov Today. 2006;11:245–53. https://doi.org/10.1016/S1359-6446(05)03662-7

    Article  CAS  PubMed  Google Scholar 

  21. Brittain JM, Duarte DB, Wilson SM, Zhu W, Ballard C, Johnson PL, et al. Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca(2)(+) channel complex. Nat Med. 2011;17:822–9. https://doi.org/10.1038/nm.2345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Moutal A, Wang Y, Yang X, Ji Y, Luo S, Dorame A, et al. Dissecting the role of the CRMP2-neurofibromin complex on pain behaviors. Pain. 2017;158:2203–21. https://doi.org/10.1097/j.pain.0000000000001026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hoppe-Seyler F, Crnkovic-Mertens I, Tomai E, Butz K. Peptide aptamers: specific inhibitors of protein function. Curr Mol Med. 2004;4:529–38.

    Article  CAS  Google Scholar 

  24. Brittain JM, Piekarz AD, Wang Y, Kondo T, Cummins TR, Khanna R. An atypical role for collapsin response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltage-gated calcium channels. J Biol Chem. 2009;284:31375–90. https://doi.org/10.1074/jbc.M109.009951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Francois-Moutal L, Wang Y, Moutal A, Cottier KE, Melemedjian OK, Yang X, et al. A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors. Pain. 2015;156:1247–64. https://doi.org/10.1097/j.pain.0000000000000147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xie JY, Chew LA, Yang X, Wang Y, Qu C, Wang Y, et al. Sustained relief of ongoing experimental neuropathic pain by a CRMP2 peptide aptamer with low abuse potential. Pain. 2016;157:2124–40. https://doi.org/10.1097/j.pain.0000000000000628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Simms BA, Zamponi GW. Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron. 2014;82:24–45. https://doi.org/10.1016/j.neuron.2014.03.016

    Article  CAS  PubMed  Google Scholar 

  28. Chi XX, Schmutzler BS, Brittain JM, Wang Y, Hingtgen CM, Nicol GD, et al. Regulation of N-type voltage-gated calcium channels (Cav2.2) and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons. J Cell Sci. 2009;122:4351–62. https://doi.org/10.1242/jcs.053280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fischer G, Pan B, Vilceanu D, Hogan QH, Yu H. Sustained relief of neuropathic pain by AAV-targeted expression of CBD3 peptide in rat dorsal root ganglion. Gene Ther. 2014;21:44–51. https://doi.org/10.1038/gt.2013.56

    Article  CAS  PubMed  Google Scholar 

  30. Piekarz AD, Due MR, Khanna M, Wang B, Ripsch MS, Wang R, et al. CRMP-2 peptide mediated decrease of high and low voltage-activated calcium channels, attenuation of nociceptor excitability, and anti-nociception in a model of AIDS therapy-induced painful peripheral neuropathy. Mol Pain. 2012;8:54 https://doi.org/10.1186/1744-8069-8-54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yu H, Fischer G, Ferhatovic L, Fan F, Light AR, Weihrauch D, et al. Intraganglionic AAV6 results in efficient and long-term gene transfer to peripheral sensory nervous system in adult rats. PLoS ONE. 2013;8:e61266 https://doi.org/10.1371/journal.pone.0061266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hughes DI, Scott DT, Todd AJ, Riddell JS. Lack of evidence for sprouting of Abeta afferents into the superficial laminas of the spinal cord dorsal horn after nerve section. J Neurosci. 2003;23:9491–9.

    Article  CAS  Google Scholar 

  33. Yu H, Pan B, Weyer A, Wu HE, Meng J, Fischer G, et al. CaMKII controls whether touch is painful. J Neurosci. 2015;35:14086–102. https://doi.org/10.1523/JNEUROSCI.1969-15.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. D’Arco M, Margas W, Cassidy JS, Dolphin AC. The upregulation of alpha2delta-1 subunit modulates activity-dependent Ca2+signals in sensory neurons. J Neurosci. 2015;35:5891–903. https://doi.org/10.1523/JNEUROSCI.3997-14.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lu SG, Zhang XL, Luo ZD, Gold MS. Persistent inflammation alters the density and distribution of voltage-activated calcium channels in subpopulations of rat cutaneous DRG neurons. Pain. 2010;151:633–43. https://doi.org/10.1016/j.pain.2010.08.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hoppa MB, Lana B, Margas W, Dolphin AC, Ryan T. A. alpha2delta expression sets presynaptic calcium channel abundance and release probability. Nature. 2012;486:122–5. https://doi.org/10.1038/nature11033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Westenbroek RE, Hell JW, Warner C, Dubel SJ, Snutch TP, Catterall WA. Biochemical properties and subcellular distribution of an N-type calcium channel alpha 1 subunit. Neuron. 1992;9:1099–115.

    Article  CAS  Google Scholar 

  38. Cizkova D, Marsala J, Lukacova N, Marsala M, Jergova S, Orendacova J, et al. Localization of N-type Ca2+ channels in the rat spinal cord following chronic constrictive nerve injury. Exp Brain Res. 2002;147:456–63. https://doi.org/10.1007/s00221-002-1217-3

    Article  CAS  PubMed  Google Scholar 

  39. Todd AJ. Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci. 2010;11:823–36. https://doi.org/10.1038/nrn2947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wilson SM, Brittain JM, Piekarz AD, Ballard CJ, Ripsch MS, Cummins TR, et al. Further insights into the antinociceptive potential of a peptide disrupting the N-type calcium channel-CRMP-2 signaling complex. Channels. 2011;5:449–56. https://doi.org/10.4161/chan.5.5.17363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Xiang H, Liu Z, Wang F, Xu H, Roberts C, Fischer G, et al. Primary sensory neuron-specific interference of TRPV1 signaling by AAV-encoded TRPV1 peptide aptamer attenuates neuropathic pain. Mol Pain. 2017;13:1744806917717040 https://doi.org/10.1177/1744806917717040

    Article  PubMed  PubMed Central  Google Scholar 

  42. Swett JE, Torigoe Y, Elie VR, Bourassa CM, Miller PG. Sensory neurons of the rat sciatic nerve. Exp Neurol. 1991;114:82–103.

    Article  CAS  Google Scholar 

  43. Heinke B, Balzer E, Sandkuhler J. Pre- and postsynaptic contributions of voltage-dependent Ca2+channels to nociceptive transmission in rat spinal lamina I neurons. Eur J Neurosci. 2004;19:103–11.

    Article  CAS  Google Scholar 

  44. Rycroft BK, Vikman KS, Christie MJ. Inflammation reduces the contribution of N-type calcium channels to primary afferent synaptic transmission onto NK1 receptor-positive lamina I neurons in the rat dorsal horn. J Physiol. 2007;580:883–94. https://doi.org/10.1113/jphysiol.2006.125880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chai Z, Wang C, Huang R, Wang Y, Zhang X, Wu Q, et al. CaV2.2 gates calcium-independent but voltage-dependent secretion in mammalian sensory neurons. Neuron. 2017;96:1317–26. https://doi.org/10.1016/j.neuron.2017.10.028. e1314

    Article  CAS  PubMed  Google Scholar 

  46. Zhang FX, Gadotti VM, Souza IA, Chen L, Zamponi GW. BK potassium channels suppress cavalpha2delta subunit function to reduce inflammatory and neuropathic pain. Cell Rep. 2018;22:1956–64. https://doi.org/10.1016/j.celrep.2018.01.073

    Article  CAS  PubMed  Google Scholar 

  47. Bezprozvanny I, Zhong P, Scheller RH, Tsien RW. Molecular determinants of the functional interaction between syntaxin and N-type Ca2+ channel gating. Proc Natl Acad Sci USA. 2000;97:13943–8. https://doi.org/10.1073/pnas.220389697

    Article  CAS  PubMed  Google Scholar 

  48. Cassidy JS, Ferron L, Kadurin I, Pratt WS, Dolphin AC. Functional exofacially tagged N-type calcium channels elucidate the interaction with auxiliary alpha2delta-1 subunits. Proc Natl Acad Sci USA. 2014;111:8979–84. https://doi.org/10.1073/pnas.1403731111

    Article  CAS  PubMed  Google Scholar 

  49. Diverse-Pierluissi M, Dunlap K. Interaction of convergent pathways that inhibit N-type calcium currents in sensory neurons. Neuroscience. 1995;65:477–83.

    Article  CAS  Google Scholar 

  50. Kadurin I, Rothwell SW, Lana B, Nieto-Rostro M, Dolphin AC. LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary alpha2delta-1 subunit. Sci Rep. 2017;7:43802 https://doi.org/10.1038/srep43802

    Article  PubMed  PubMed Central  Google Scholar 

  51. Leroy J, Richards MW, Butcher AJ, Nieto-Rostro M, Pratt WS, Davies A, et al. Interaction via a key tryptophan in the I-II linker of N-type calcium channels is required for beta1 but not for palmitoylated beta2, implicating an additional binding site in the regulation of channel voltage-dependent properties. J Neurosci. 2005;25:6984–96. https://doi.org/10.1523/JNEUROSCI.1137-05.2005

    Article  CAS  PubMed  Google Scholar 

  52. Omote K, Kawamata M, Satoh O, Iwasaki H, Namiki A. Spinal antinociceptive action of an N-Type voltage-dependent calcium channel blocker and the synergistic interaction with morphine. Anesthesiology. 1996;84:636–43.

    Article  CAS  Google Scholar 

  53. Sheng ZH, Rettig J, Cook T, Catterall WA. Calcium-dependent interaction of N-type calcium channels with the synaptic core complex. Nature. 1996;379:451–4. https://doi.org/10.1038/379451a0

    Article  CAS  PubMed  Google Scholar 

  54. Ju W, Li Q, Allette YM, Ripsch MS, White FA & Khanna R. Suppression of pain-related behavior in two distinct rodent models of peripheral neuropathy by a homopolyarginine-conjugated CRMP2 peptide. J Neurochem. https://doi.org/10.1111/jnc.12070 (2012).

    Article  CAS  Google Scholar 

  55. Ripsch MS, Ballard CJ, Khanna M, Hurley JH, White FA, Khanna R. A Peptide uncoupling crmp-2 from the presynaptic ca(2+) channel complex demonstrates efficacy in animal models of migraine and aids therapy-induced neuropathy. Transl Neurosci. 2012;3:1–8. https://doi.org/10.2478/s13380-012-0002-4

    Article  PubMed  PubMed Central  Google Scholar 

  56. Ip JP, Fu AK, Ip NY. CRMP2: functional roles in neural development and therapeutic potential in neurological diseases. Neuroscientist. 2014;20:589–98. https://doi.org/10.1177/1073858413514278

    Article  CAS  PubMed  Google Scholar 

  57. Suzuki Y, Nakagomi S, Namikawa K, Kiryu-Seo S, Inagaki N, Kaibuchi K, et al. Collapsin response mediator protein-2 accelerates axon regeneration of nerve-injured motor neurons of rat. J Neurochem. 2003;86:1042–50.

    Article  CAS  Google Scholar 

  58. Kamiya Y, Saeki K, Takiguchi M. CDK5, CRMP2 and NR2B in spinal dorsal horn and dorsal root ganglion have different role in pain signaling between neuropathic pain model and inflammatory pain model. Eur J Anaesthesiol. 2013;30:214.

    Article  Google Scholar 

  59. Zhang JN, Koch JC. Collapsin response mediator protein-2 plays a major protective role in acute axonal degeneration. Neural Regen Res. 2017;12:692–5. https://doi.org/10.4103/1673-5374.206631

    Article  PubMed  PubMed Central  Google Scholar 

  60. Moutal A, Luo S, Largent-Milnes, TM, Vanderah TW, Khanna R. Cdk5-mediated CRMP2 phosphorylation is necessary and sufficient for peripheral neuropathic pain. Neurobiol Pain. In press, https://doi.org/10.1016/j.ynpai.2018.1007.1003 (2018).

  61. Chapman V, Suzuki R, Dickenson AH. Electrophysiological characterization of spinal neuronal response properties in anaesthetized rats after ligation of spinal nerves L5-L6. J Physiol. 1998;507:881–94.

    Article  CAS  Google Scholar 

  62. Takaishi K, Eisele JH Jr., Carstens E. Behavioral and electrophysiological assessment of hyperalgesia and changes in dorsal horn responses following partial sciatic nerve ligation in rats. Pain. 1996;66:297–306.

    Article  CAS  Google Scholar 

  63. Palecek J, Paleckova V, Dougherty PM, Carlton SM, Willis WD. Responses of spinothalamic tract cells to mechanical and thermal stimulation of skin in rats with experimental peripheral neuropathy. J Neurophysiol. 1992;67:1562–73. https://doi.org/10.1152/jn.1992.67.6.1562

    Article  CAS  PubMed  Google Scholar 

  64. Laird JM, Bennett GJ. An electrophysiological study of dorsal horn neurons in the spinal cord of rats with an experimental peripheral neuropathy. J Neurophysiol. 1993;69:2072–85. https://doi.org/10.1152/jn.1993.69.6.2072

    Article  CAS  PubMed  Google Scholar 

  65. Brustovetsky T, Pellman JJ, Yang XF, Khanna R, Brustovetsky N. Collapsin response mediator protein 2 (CRMP2) interacts with N-methyl-D-aspartate (NMDA) receptor and Na+/Ca2+exchanger and regulates their functional activity. J Biol Chem. 2014;289:7470–82. https://doi.org/10.1074/jbc.M113.518472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dustrude ET, Wilson SM, Ju W, Xiao Y, Khanna R. CRMP2 protein SUMOylation modulates NaV1.7 channel trafficking. J Biol Chem. 2013;288:24316–31. https://doi.org/10.1074/jbc.M113.474924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Brittain JM, Pan R, You H, Brustovetsky T, Brustovetsky N, Zamponi GW, et al. Disruption of NMDAR-CRMP-2 signaling protects against focal cerebral ischemic damage in the rat middle cerebral artery occlusion model. Channels (Austin) 2012;6:52–59.

    Article  CAS  Google Scholar 

  68. Kanellopoulos AH, Koenig J, Huang H, Pyrski M, Millet Q, Lolignier S, et al. Mapping protein interactions of sodium channel NaV1.7 using epitope-tagged gene-targeted mice. Embo J. 2018;37:427–45. https://doi.org/10.15252/embj.201796692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sumi T, Imasaki T, Aoki M, Sakai N, Nitta E, Shirouzu M, et al. Structural insights into the altering function of CRMP2 by phosphorylation. Cell Struct Funct. 2018;43:15–23. https://doi.org/10.1247/csf.17025

    Article  PubMed  Google Scholar 

  70. Wilson SM, Ki Yeon S, Yang XF, Park KD, Khanna R. Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3ss and CDK5 following traumatic brain injury. Front Cell Neurosci. 2014;8:135 https://doi.org/10.3389/fncel.2014.00135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Brittain JM, Wang Y, Eruvwetere O, Khanna R. Cdk5-mediated phosphorylation of CRMP-2 enhances its interaction with CaV2.2. FEBS Lett. 2012;586:3813–8. https://doi.org/10.1016/j.febslet.2012.09.022

    Article  CAS  PubMed  Google Scholar 

  72. Bolash RB, Niazi T, Kumari M, Azer G, Mekhail N. Efficacy of a targeted drug delivery on-demand bolus option for chronic pain. Pain Pract. 2018;18:305–13. https://doi.org/10.1111/papr.12602

    Article  PubMed  Google Scholar 

  73. Hayek SM, Sweet JA, Miller JP, Sayegh RR. Successful management of corneal neuropathic pain with intrathecal targeted drug delivery. Pain Med. 2016;17:1302–7. https://doi.org/10.1093/pm/pnv058

    Article  PubMed  Google Scholar 

  74. Berta T, Qadri Y, Tan PH, Ji RR. Targeting dorsal root ganglia and primary sensory neurons for the treatment of chronic pain. Expert Opin Ther Targets. 2017;21:695–703. https://doi.org/10.1080/14728222.2017.1328057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Guha D, Shamji MF. The dorsal root Ganglion in the pathogenesis of chronic neuropathic pain. Neurosurgery. 2016;63:118–26. https://doi.org/10.1227/NEU.0000000000001255

    Article  PubMed  Google Scholar 

  76. Hogan QH. Labat lecture: the primary sensory neuron: where it is, what it does, and why it matters. Reg Anesth Pain Med. 2010;35:306–11. https://doi.org/10.1097/AAP.0b013e3181d2375e

    Article  PubMed  PubMed Central  Google Scholar 

  77. Terashima T, Ogawa N, Nakae Y, Sato T, Katagi M, Okano J, et al. Gene therapy for neuropathic pain through siRNA-IRF5 gene delivery with homing peptides to microglia. Mol Ther Nucleic Acids. 2018;11:203–15. https://doi.org/10.1016/j.omtn.2018.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zheng Y, Sethi R, Mangala LS, Taylor C, Goldsmith J, Wang M, et al. Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation. Nat Commun. 2018;9:476 https://doi.org/10.1038/s41467-017-02811-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Fischer G, Kostic S, Nakai H, Park F, Sapunar D, Yu H, et al. Direct injection into the dorsal root ganglion: technical, behavioral, and histological observations. J Neurosci Methods. 2011;199:43–55.

    Article  Google Scholar 

  80. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53:55–63.

    Article  CAS  Google Scholar 

  81. Wu HE, Gemes G, Zoga V, Kawano T, Hogan QH. Learned avoidance from noxious mechanical simulation but not threshold semmes weinstein filament stimulation after nerve injury in rats. J Pain. 2010;11:280–6. https://doi.org/10.1016/j.jpain.2009.07.011

    Article  PubMed  Google Scholar 

  82. Yu H, Fischer G, Jia G, Reiser J, Park F, Hogan QH. Lentiviral gene transfer into the dorsal root ganglion of adult rats. Mol Pain. 2011;7:63.

    Article  CAS  Google Scholar 

  83. Liu Z, Wang F, Fischer G, Hogan QH & Yu H. Peripheral nerve injury induces loss of nociceptive neuron-specific Galphai-interacting protein in neuropathic pain rat. Mol Pain. https://doi.org/10.1177/1744806916646380 (2016).

    Article  Google Scholar 

  84. Ramer MS, Duraisingam I, Priestley JV, McMahon SB. Two-tiered inhibition of axon regeneration at the dorsal root entry zone. J Neurosci. 2001;21:2651–60.

    Article  CAS  Google Scholar 

  85. Xiang H, Xu H, Fan F, Shin SM, Hogan QH & Yu H. Glial fibrillary acidic protein promoter determines transgene expression in satellite glial cells following intraganglionic adeno-associated virus delivery in adult rats. J Neurosci Res. https://doi.org/10.1002/jnr.24183 (2017).

    Article  Google Scholar 

Download references

Acknowledgements

This research was supported by a grant from the Department of Veterans Affairs Rehabilitation Research and Development I01RX001940 (to Q. Hogan). R. Khanna is supported by grants from National Institutes of Health Awards (1R01NS098772 and 1R01DA042852). H. Xiang was a recipient of National Natural Science Foundation of China (81802190, 81772412). Y. Cai was a recipient of Chinese Scholarship Council.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Hongwei Yu, Seung Min Shin, Hongfei Xiang, Dongman Chao, Yongsong Cai, Hao Xu, Bin Pan & Quinn H. Hogan

  2. Zablocki Veterans Affairs Medical Center, Milwaukee, WI, 53295, USA

    Hongwei Yu, Seung Min Shin & Quinn H. Hogan

  3. Department of Orthopedic Surgery, Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China

    Hongfei Xiang & Hao Xu

  4. Xi’an Jiaotong University Health Science Center, 710061, Xi’an, Shaanxi, PR China

    Yongsong Cai

  5. Departments of Pharmacology, Neuroscience and Anesthesiology, College of Medicine, University of Arizona, Tucson, AZ, 85724, USA

    Rajesh Khanna

Authors
  1. Hongwei Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seung Min Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongfei Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dongman Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yongsong Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hao Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rajesh Khanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bin Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Quinn H. Hogan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hongwei Yu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, H., Shin, S., Xiang, H. et al. AAV-encoded CaV2.2 peptide aptamer CBD3A6K for primary sensory neuron-targeted treatment of established neuropathic pain. Gene Ther 26, 308–323 (2019). https://doi.org/10.1038/s41434-019-0082-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41434-019-0082-7

This article is cited by

Search

Advanced search

Quick links