title: Spinal NF-kB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity.
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-1 beta receptor antagonist or caspase-1 inhibitor. In view of the fact that interleukin-1 beta (IL-1 beta) is the major inducer of spinal COX-2 upregulation following CFA injection, our results suggest that IL-1 beta-induced spinal COX-2 upregulation and pain hypersensitivity following peripheral inflammation are mediated through the activation of the NF-kB-associated pathways.
authors.affiliation: Department of Anatomy, Pain and Neural Injury Research Center, MRC, School of Medicine, Kyungpook National University, 2-101, Dongin-Dong, Daegu, 700-422, South Korea.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lee
authors.forename: Bong-Seok
authors.initials: BS
authors.lastname: Kang
authors.forename: Hye-Lim
authors.initials: HL
authors.lastname: Lee
authors.forename: Sun-Joo
authors.initials: SJ
authors.lastname: Son
authors.forename: Sung-Hun
authors.initials: SH
authors.lastname: Hwang
authors.forename: Dong-Sun
authors.initials: DS
authors.lastname: Kim
authors.forename: Jae-Sik
authors.initials: JS
authors.lastname: Park
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Cho
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2; D004745:Enkephalins / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005620:Freund's Adjuvant / Q000633:toxicity; D015870:Gene Expression; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology; D006930:Hyperalgesia / Q000503:physiopathology*; D007249:Inflammation / Q000139:chemically induced; D007278:Injections, Spinal; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis* / Q000187:drug effects; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D010146:Pain / Q000503:physiopathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000187:drug effects; D011498:Protein Precursors / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000008:administration & dosage; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D015854:Up-Regulation
chemical_list: D004745:Enkephalins; D004791:Enzyme Inhibitors; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D007527:Isoenzymes; D016328:NF-kappa B; D011498:Protein Precursors; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D005620:Freund's Adjuvant; C033660:preproenkephalin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases