Spinal NF-kB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity

Kyung Min Lee, Bong Seok Kang, Hye Lim Lee, Sun Joo Son, Sung Hun Hwang, Dong Sun Kim, Jae Sik Park, Hee Jung Cho

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226 Scopus citations

Abstract

Cyclooxygenase-2 (COX-2) is a major contributor to the elevation of spinal prostaglandin E2 which augments the processing of nociceptive stimuli following peripheral inflammation, and dynorphin has been shown to have an important role in acute and chronic pain states. Moreover, the transcription factor, nuclear factor-kappa B (NF-kB), regulates the expressions of both COX-2 and dynorphin. To elucidate the role of spinal NF-kB in the induction of inflammatory pain hypersensitivity, we examined whether activated NF-kB affects pain behavior and the expressions of the mRNAs of COX-2 and prodynorphin following peripheral inflammation. Intrathecal pretreatment with different NF-kB inhibitors, namely, NF-kB decoy or pyrrolidine dithiocarbamate, significantly reduced mechanical allodynia and thermal hyperalgesia following unilateral hindpaw inflammation evoked by complete Freund's adjuvant (CFA). These NF-kB inhibitors also suppressed the activation of spinal NF-kB and the subsequent remarkable elevation of spinal COX-2 mRNA, but not that of prodynorphin mRNA. In addition, the activation of spinal NF-kB following CFA injection was inhibited by intrathecal pretreatments with interleukin-1β receptor antagonist or caspase-1 inhibitor. In view of the fact that interleukin-1 beta (IL-1β) is the major inducer of spinal COX-2 upregulation following CFA injection, our results suggest that IL-1β-induced spinal COX-2 upregulation and pain hypersensitivity following peripheral inflammation are mediated through the activation of the NF-kB-associated pathways.

Original languageEnglish
Pages (from-to)3375-3381
Number of pages7
JournalEuropean Journal of Neuroscience
Volume19
Issue number12
DOIs
StatePublished - Jun 2004

Keywords

  • COX-2
  • IL-1β
  • Inflammatory pain
  • NF-kB
  • Spinal cord

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