Transcriptional Profiling of TGF-β Superfamily Members in Lumbar DRGs of Rats Following Sciatic Nerve Axotomy and Activin C Inhibits Neuropathic Pain

Abstract

Background: Neuroinflammation and cytokines play critical roles in neuropathic pain and axon degeneration/regeneration. Cytokines of transforming growth factor-β superfamily have implications in pain and injured nerve repair processing. However, the transcriptional profiles of the transforming growth factor-β superfamily members in dorsal root ganglia under neuropathic pain and axon degeneration/regeneration conditions remain elusive. Objective: We aimed to plot the transcriptional profiles of transforming growth factor-β superfamily components in lumbar dorsal root ganglia of nerve axotomized rats and to further verify the profiles by testing the analgesic effect of activin C, a representative cytokine, on neuropathic pain. Methods: Adult male rats were axotomized in sciatic nerves and lumbar dorsal root ganglia were isolated for total RNA extraction or section. A custom microarray was developed and employed to plot the gene expression profiles of transforming growth factor-β superfamily components. Real-time RT-PCR was used to confirm changes in the expression of activin/inhibin family genes, and then in situ hybridization was performed to determine the cellular locations of activin βC mRNAs. Rat spared nerve injury model was performed and pain test was employed to determine the effect of activin C on neuropathic pain. Results: The expression of transforming growth factor-β superfamily cytokines and their signaling, including some receptors and signaling adaptors, were robustly upregulated. Activin βC subunit mRNAs were expressed in the small-diameter dorsal root ganglion neurons and upregulated after axotomy. Single intrathecal injection of activin C inhibited neuropathic pain in spared nerve injury model. Conclusion: This is the first report to investigate the transcriptional profiles of members of transforming growth factor-β superfamily in axotomized dorsal root ganglia. The distinct cytokine profiles observed here might provide clues toward further study of the role of transforming growth factor-β superfamily in the pathogenesis of neuropathic pain and axon degeneration/regeneration after peripheral nerve injury.