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

Background: Neuroinflammation and cytokines play critical roles in neuropathic pain and axon degeneration/regeneration. Cytokines of transforming growth factor-beta superfamily have implications in pain and injured nerve repair processing. However, the transcriptional profiles of the transforming growth factor-beta 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-beta superfamily components in lumbar dorsal root ganglia of sciatic 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-beta 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 inhibin a, activin beta C, BMP-5 and GDF-9 mRNAs. The rat spared nerve injury model was performed, and a pain test was employed to determine the effect of activin C on neuropathic pain. Results: The expression of transforming growth factor-beta superfamily cytokines and their signaling, including some receptors and signaling adaptors, were robustly upregulated. Activin beta C 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-beta 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-beta superfamily in the pathogenesis of neuropathic pain and axon degeneration/regeneration after peripheral nerve injury.