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RNA interference-mediated gene silence of the NR1 subunit of the NMDA receptor by subcutaneous injection of vector-encoding short hairpin RNA reduces formalin-induced nociception in the rat

Tan, Ping-Henga,b,*; Yu, Shang-Wonc; Lin, Victor Chia-Hsiangd; Liu, Chien-Chenga; Chien, Chih-Fang Changa

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doi: 10.1016/j.pain.2010.11.026
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There is accumulating evidence to implicate the importance of N-methyl-d-aspartate (NMDA) receptors to the induction and maintenance of central sensitization during pain states. However, the use of NMDA receptor antagonists can often be limited by serious central nervous system side effects. The development of peripheral NMDA receptor antagonists that do not interfere with central glutamate processing can avoid adverse effects of the central nervous system. RNA interference is an evolutionarily conserved mechanism for silencing gene expression in which a targeted mRNA is degraded by a double-stranded RNA sequence known as a small interfering RNA (siRNA). siRNAs can be derived from short hairpin (sh) RNAs, which can be expressed from plasmids or viral vectors to achieve long-term gene silencing. In this study, we examined the effect of gene silence and antinociception on formalin-induced pain by subcutaneous injection of vector-encoding shRNA targeting the NR1 subunit of the NMDA receptor. The results revealed that subcutaneous injection of vector-expressing NR1 shRNA could effectively diminish the nociception induced by formalin stimuli and inhibit gene expression of NR1 evidenced by a decreased level of mRNA and protein. The effect of antinociception and inhibition of NR1 expression by NR1 shRNA persisted for about 14 days. The data suggest that NR1 shRNA has therapeutic potential to provide long-term treatment of pathological pain that is induced or maintained by peripheral nociceptor activity.

Subcutaneous injection of NR1 short hairpin RNA has the therapeutic potential of providing long-term treatment of pathological pain that is induced or maintained by peripheral nociceptor activity.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

aDepartment of Anesthesiology, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan, ROC

bDepartment of Biomedical Engineering, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan, ROC

cDepartment of Orthopaedic Surgery, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan, ROC

dDepartment of Urology, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan, ROC

*Corresponding author. Address: Department of Anesthesiology, Department of Biomedical Engineering, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan. Tel.: +886 7 6150011x2532; fax: +886 7 3423348.

E-mail: tanphphd@hotmail.com

Submitted April 1, 2010; revised November 11, 2010; accepted November 22, 2010.

© 2011 Lippincott Williams & Wilkins, Inc.
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