Inhibitor kappa B kinase beta dependent cytokine upregulation in nociceptive neurons contributes to nociceptive hypersensitivity after sciatic nerve injury.

Abstract

UNLABELLED:

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.

PERSPECTIVE:

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: Maike Kanngiesser, Annett Häussler, Thekla Myrczek, Nele Küsener, Hee-Young Lim, Gerd Geisslinger, Ellen Niederberger, Irmgard Tegeder
• Journal: The journal of pain (J Pain) Vol. 13 Issue 5 Pg. 485-97 (May 2012) ISSN: 1528-8447 [Electronic] United States
• PMID: 22564672 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Enzyme Inhibitors
• I-kappa B Kinase
• Calcium

Topics

• Analysis of Variance
• Animals
• Calcium (metabolism)
• Cells, Cultured
• Cytokines (genetics, metabolism, pharmacology)
• Disease Models, Animal
• Drug Delivery Systems
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Ganglia, Spinal (pathology)
• Hyperalgesia (drug therapy, etiology, genetics)
• I-kappa B Kinase (deficiency, metabolism, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nociceptors (drug effects, metabolism)
• Pain Threshold (drug effects)
• Reaction Time (drug effects, genetics)
• Sciatic Neuropathy (complications, drug therapy, pathology)
• Spinal Cord (drug effects, metabolism, pathology)
• Time Factors
• Up-Regulation (drug effects, genetics, physiology)