title: Inhibitor kappa B kinase beta dependent cytokine upregulation in nociceptive neurons contributes to nociceptive hypersensitivity after sciatic nerve injury.
abstract: Inhibitor kappa B kinase (IKK)-mediated nuclear factor-kappa B (NF-κB) activation is a major pathway for transcriptional control of various pro-inflammatory factors. We here assessed whether activation of this pathway specifically in primary nociceptive neurons of the dorsal root ganglia (DRG) contributes to the development of nociceptive hypersensitivity. Mice carrying a cre-loxP-mediated deletion of inhibitor kappa B kinase beta (IKKβ) in DRG neurons were protected from nerve injury-evoked allodynia and hyperalgesia. This effect was mimicked by systemic treatment with an IKKβ inhibitor but was not observed upon specific inhibition of IKKβ in the spinal cord, suggesting a specific role of IKKβ in the peripheral neurons. The deletion of IKKβ in DRG neurons did not affect constitutive neuronal NF-κB activity, but reduced nerve injury-evoked NF-κB stimulation in the DRG and was associated with reduced upregulation of interleukin-16, monocyte chemoattractant protein-1/chemokine (CC motif) ligand 2 (MCP-1/CCL2), and tumor necrosis factor alpha (TNFα) in the DRG. These cytokines evoked a rapid rise of intracellular calcium in subsets of primary DRG neurons. The results suggest that IKKβ-mediated NF-κB stimulation in injured primary sensory neurons promotes cytokine and chemokine production and contributes thereby to the development of chronic pain.
  
  
  CONCLUSIONS
  Inhibitors of IKK that do not pass the blood-brain barrier and act only in the periphery might be useful for reduction of the pro-inflammatory response in peripheral DRG neurons and reduce thereby nerve injury-evoked pain without affecting neuroprotective effects of NF-κB in the central nervous system.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Kanngiesser
authors.forename: Annett
authors.initials: A
authors.lastname: Häussler
authors.forename: Thekla
authors.initials: T
authors.lastname: Myrczek
authors.forename: Nele
authors.initials: N
authors.lastname: Küsener
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Lim
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Ellen
authors.initials: E
authors.lastname: Niederberger
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005727:Ganglia, Spinal / Q000473:pathology*; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics; D051550:I-kappa B Kinase / Q000172:deficiency / Q000378:metabolism* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D020426:Sciatic Neuropathy / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D051550:I-kappa B Kinase; D002118:Calcium