Prevention of neuropathic pain in an animal model of spare nerve injury following oral immunization with recombinant adenovirus serotype 5-mediated nr2b gene transfer

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

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Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS DISCUSSION OF SPINAL CORD NEURONS APOPTOSIS AND NEUROPROTECTION MECHANISM OF NGF GENE TRANSFECTION MEDIATED BY RECOMBINANT

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REFERENCES * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * Yung KKL . Localization of glutamate receptors in dorsal horn of rat spinal cord. _NeuroReport_ 1998; 9: 1639–1644. Article  CAS  PubMed 

Google Scholar  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  *

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  * 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  * 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  * 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  * 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  * Dixon WJ . Efficient analysis of

experimental observations. _Annu Rev Pharmacol Toxicol_ 1980; 20: 441–462. Article  CAS  PubMed  Google Scholar  * 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  Download references 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).

AUTHOR INFORMATION Author notes * G-M Wang and X-B Tian: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * 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 * Department of Anesthesiology,

Shandong Provincial Hospital, Shandong, China G-M Wang * Department of Anesthesiology, Second Hospital of Shanxi Medical University, Shanxi, China J-P Chen Authors * G-M Wang View author

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AUTHOR Correspondence to Y-K Tian. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 23 March 2007 * Revised: 06 August 2007 * Accepted: 06 August 2007 * Published: 25 October 2007 * Issue Date: December

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not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * neuropathic pain * adenovirus serotype 5 vector *

genetic immunization * NR2B