Small interfering RNA-mediated knockdown of NF-κBp65 attenuates neuropathic pain following peripheral nerve injury in rats

Eur J Pharmacol. 2012 May 5;682(1-3):79-85. doi: 10.1016/j.ejphar.2012.02.017. Epub 2012 Feb 21.

Abstract

Recent reports show that the nuclear factor-κB (NF-κB) can control numerous genes encoding inflammatory and nociceptive mediators and play an important role in the development of central pain sensitization. The aim of the present study is to assess the role of NF-κB signal pathway and its downstream pro-inflammatory cytokines in the modulation of neuropathic pain, by using small interfering RNAs (siRNAs) technique, which has been shown to result in potent, long-lasting post-transcriptional silencing of specific genes. We developed a highly efficient method of lentivirus-mediated delivery of short-hairpin RNA (shRNA) targeting NF-κBp65 for gene silencing. This method successfully transduced LV-shNF-κBp65 into cultured spinal cord neurons in vitro and spinal cord cells in vivo, inhibited the expression of NF-κBp65 and pro-inflammatory factors (TNF-α, IL-1β and IL-6) and alleviated mechanical allodynia and thermal hyperalgesia for more than 4weeks in chronic constriction injury (CCI) model of rats. Taken together, our results suggest that siRNA against NF-κBp65 is a potential strategy for analgesia. Furthermore, the lentiviral vector derived shRNA approach shows a great promise for the management of neuropathic pain and the study of functional NF-κBp65 gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Constriction
  • Down-Regulation / genetics
  • Gene Knockdown Techniques*
  • Genetic Vectors / genetics*
  • Hyperalgesia / complications
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • Lentivirus / genetics
  • Male
  • Neuralgia / complications
  • Neuralgia / genetics*
  • Neurons / metabolism
  • Peripheral Nerve Injuries / complications*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics*
  • Rats
  • Rats, Sprague-Dawley
  • Spinal Cord / pathology
  • Transcription Factor RelA / deficiency*
  • Transcription Factor RelA / genetics*
  • Transcription Factor RelA / metabolism
  • Transduction, Genetic
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Interleukin-1beta
  • Interleukin-6
  • RNA, Messenger
  • RNA, Small Interfering
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha