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. 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.