IκB kinase β inhibitor downregulates pain-related neuropeptide production in the sensory neurons innervating injured lumbar intervertebral discs in the dorsal root ganglia of rats

摘要

Background context: Nuclear factor-κB (NF-κB) is an essential gene transcriptional regulator of inflammatory cytokines, and it plays important roles in numerous conditions, including inflammatory and neuropathic pain, especially when discogenic pain is involved. Phosphorylation of IκB protein through IκB kinase (IKK) is the first step in the activation of NF-κB activation and the upregulation of NF-κB-responsive genes. Purpose: To investigate whether IKK inhibition alters the properties of pain-related neuropeptides in the rat lumbar degenerative intervertebral disc (IVD) model. Study design: Retrograde neurotracing and immunofluorescent investigation of pain-related neuropeptide (calcitonin gene-related peptide [CGRP]) in the sensory innervation of injured lumbar IVD in rat dorsal root ganglia (DRGs). Methods: Forty female Sprague-Dawley rats were equally divided into four groups: naive, sham, and two agent-treated groups (vehicle [saline] group and anti-IKKβ [IMD-0560, IKKβ inhibitor] group). The L5-L6 IVDs of the agent-treated rats were exposed and injured by repeated punctures. The retrograde neurotracer Fluoro-Gold (FG) and corresponding treatment agents were intradiscally applied. In the sham group, FG alone was applied onto uninjured IVDs. One week later, L1-L3 DRGs were harvested and immunolabeled for CGRP as a pain marker. The proportions of FG-labeled CGRP-immunoreactive (-ir) DRG neurons were assessed. Results: Fluoro-Gold-labeled DRG neurons were almost equally prevalent at each DRG level. The proportions of FG-labeled CGRP-ir DRG neurons in the two agent-treated groups were significantly increased in comparison with those in the naive and the sham groups (p<.05) and were significantly decreased in the anti-IKKβ group in comparison with that in the vehicle group (p<.05). Conclusions: The neuropeptide CGRP as a pain marker was upregulated in DRG neurons innervating the injured IVDs, and intradiscal inhibition of IKKβ significantly suppressed CGRP production in the DRG neurons innervating the rat IVD, suggesting the possible analgesic effect of IKKβ inhibition in discogenic pain.