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Prevention of neuropathic pain in an animal model of spare nerve injury following oral immunization with recombinant adenovirus serotype 5-mediated NR2B gene transfer

Gene Therapy volume 14, pages 1681–1687 (2007)Cite this article

A Corrigendum to this article was published on 05 February 2008

Abstract

Spinal N-methyl-D-aspartate receptor 2B subunit (NR2B)-increased expression plays an important role in the facilitation and maintenance of the persistent pain state due to peripheral nerve injury. A vaccination strategy to reduce the expression of brain protein is feasible and may have therapeutic potential for neurological disorders. Thus, we investigated the effect of oral immunization with recombinant adenovirus serotype 5-mediated NR2B gene transfer (rAd5/NR2B) for the modulation of neuropathic pain. After peroral administration of the rAd5/NR2B vaccine, transgene NR2B expression persisted for at least a week and was associated with the induction of high serum titers of NR2B-specific antibodies. Following the occurrence of mechanical allodynia due to peripheral nerve injury, NR2B-specific antibodies could pass the blood–brain barrier, transport and subsequently bind to the spinal NR2B protein. The humoral immunoresponse results in the strong antiallodynia in the spared nerve injury animal model. These data proved the feasibility of oral immunization with rAd5/NR2B for the prevention of neuropathic pain.

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References

  1. 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: 881–894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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: 881–894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Woolf CJ, Thompson SW . The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain 1991; 44: 293–299.

    Article  CAS  PubMed  Google Scholar 

  4. Sotgiu ML, Biella G . Differential effects of MK-801, an N-methyl-D-aspartate non-competitive antagonist, on the dorsal horn neuron hyperactivity and hyperexcitability in neuropathic rats. Neurosci Lett 2000; 283: 153–156.

    Article  CAS  PubMed  Google Scholar 

  5. Quartaroli M, Carignani C, Dal Forno G, Mugnaini M, Ugolini A, Arban R et al. Potent antihyperalgesic activity without tolerance produced by glycine site antagonist of N-methyl-D-aspartate receptor GV196771A. J Pharmacol Exp Ther 1999; 290: 158–169.

    CAS  PubMed  Google Scholar 

  6. Fairbanks CA, Schreiber KL, Brewer KL, Yu CG, Stone LS, Kitto KF et al. Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury. Proc Natl Acad Sci USA 2000; 97: 10584–10589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Martin WJ, Malmberg AB, Basbaum AI . PKCg contributes to a subset of the NMDA-dependent spinal circuits that underlie injury-induced persistent pain. J Neurosci 2001; 21: 5321–5327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tölle TR, Berthele A, Zieglgansberger W, Seeburg PH, Wisden W . The differential expression of 16 NMDA and non-NMDA receptor subunits in the rat spinal cord and in periaqueductal gray. J Neurosci 1993; 12: 5009–5028.

    Article  Google Scholar 

  9. Yung KKL . Localization of glutamate receptors in dorsal horn of rat spinal cord. NeuroReport 1998; 9: 1639–1644.

    Article  CAS  PubMed  Google Scholar 

  10. Monyer H, Burnasher N, Laurie DJ, Sakmann B, Seeburg PH . Development and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 1994; 12: 529–540.

    Article  CAS  PubMed  Google Scholar 

  11. Boyce S, Wyatt A, Webb JK, O'Donnell R, Mason G, Rigby M et al. Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn. Neuropharmacology 1999; 38: 611–623.

    Article  CAS  PubMed  Google Scholar 

  12. Tan PH, Yang LC, Shin HC, Lan KC, Cheng JT . Gene knockdown with intrathecal siRNA of NMDA receptor NR2B subunit reduces formalin-induced nociception in the rat. Gene Therapy 2005; 12: 59–66.

    Article  CAS  PubMed  Google Scholar 

  13. During MJ, Symes CW, Lawlor PA, Lin J, Dunning J, Fitzsimons HL et al. An oral vaccine againstNMDAR1 with efficacy in experimental stroke and epilepsy. Science 2000; 287: 1453–1460.

    Article  CAS  PubMed  Google Scholar 

  14. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T . Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999; 400: 173–177.

    Article  CAS  PubMed  Google Scholar 

  15. Darnell RB . Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity, and the brain. Proc Natl Acad Sci USA 1996; 93: 4529–4536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Aihara N, Tanno H, Hall JJ, Pitts LH, Noble LJ . Immunocytochemical localization of immunoglobulins in the rat brain: relationship to the blood–brain barrier. J Comp Neurol 1994; 342: 481–496.

    Article  CAS  PubMed  Google Scholar 

  17. Mayhan WG, Didion SP . Glutamate-induced disruption of the blood–brain barrier in rats. Role of nitric oxide. Stroke 1996; 27: 965–969.

    Article  CAS  PubMed  Google Scholar 

  18. Decosterd I, Woolf CJ . Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 2000; 87: 149–158.

    Article  CAS  PubMed  Google Scholar 

  19. Loftis JM, Janowsky A . The N-methyl-D-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications. Pharmacol Ther 2003; 97: 55–85.

    Article  CAS  PubMed  Google Scholar 

  20. Mittereder N, March KL, Trapnell BC . Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy. J Virol 1996; 70: 7498–7509.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Koizumi N, Mizuguchi H, Hosono T, Ishii-Watabe A, Uchida E, Utoguchi N et al. Efficient gene transfer by fiber-mutant adenoviral vectors containing RGD peptide. Biochim Biophys Acta 2001; 1568: 13–20.

    Article  CAS  PubMed  Google Scholar 

  22. Dash S, Saxena R, Myung J, Rege T, Tsuji H, Gaglio P et al. HCVRNA levels in hepatocellular carcinomas and adjacent nontumorous livers. J Virol Methods 2000; 90: 15–23.

    Article  CAS  PubMed  Google Scholar 

  23. Wei F, Wang GD, Kerchner GA, Kim SJ, Xu HM, Chen ZF et al. Genetic enhancement of inflammatory pain by forebrain NR2B overexpression. Nat Neurosci 2001; 4: 164–169.

    Article  CAS  PubMed  Google Scholar 

  24. Dixon WJ . Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol 1980; 20: 441–462.

    Article  CAS  PubMed  Google Scholar 

  25. 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. Yeast recombinase FLP functions effectively in human cells for construction of adenovirus vectors. BioTechniques 2000; 29: 524–528.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Luo Jianhong for his endowment of plasmid pcDNA3.1/NR2B. We express our gratitude to Wu Xiaobing who contributed to the construction of an adenovirus vector. This work was supported by a grant from the National Natural Science Foundation of China (30471660).

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  1. G-M Wang and X-B Tian: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    G-M Wang, X-B Tian, J-P Chen, S-B Yang, F Gao, H Yang, K An & Y-K Tian

  2. Department of Anesthesiology, Shandong Provincial Hospital, Shandong, China

    G-M Wang

  3. Department of Anesthesiology, Second Hospital of Shanxi Medical University, Shanxi, China

    J-P Chen

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  1. G-M Wang
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Correspondence to Y-K Tian.

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Wang, GM., Tian, XB., Chen, JP. et al. Prevention of neuropathic pain in an animal model of spare nerve injury following oral immunization with recombinant adenovirus serotype 5-mediated NR2B gene transfer. Gene Ther 14, 1681–1687 (2007). https://doi.org/10.1038/sj.gt.3303025

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