NIH Research Festival
Peripheral nerve lesions can cause neuropathic pain; however, the key molecule(s) that coordinate pain transmission are still poorly understood. We have shown that dual leucine zipper kinase (DLK) is a critical upstream regulator of transcriptional changes in injured sensory neurons and of a microglial response, leading to pain sensitization. Inhibition of DLK by GNE-3511 effectively prevents pain signaling and hypersensitive response after nerve damage. Here, we asked two questions: (1) is initial suppression of DLK sufficient to block pain response? (2) is delayed inhibitor treatment helpful in controlling neuropathic pain? Using a spared nerve injury (SNI) model, we assessed the induction of injury (ATF3, pc-JUN, CSF1) and microglial activation markers (IBA1) either in the DRG or the spinal cord and performed von Frey behavior assay. First, we utilized an ‚Äòon/off‚Äô approach, where we administered GNE-3511 for five days post SNI, and then discontinued it until D10. A reverse ‚Äòoff/ on‚Äô scheme was adopted to determine the delayed effect of GNE-3511 treatment. Our data revealed that the DLK pathway can be activated to initiate pain signaling days after the actual neuronal insult, and that continuous DLK inhibition is required to prevent chronic pain. Further we found that DLK inhibition is nevertheless beneficial in treating neuropathic pain days after the injury occurs. In conclusion, we show that DLK is essential not only for the onset of neuropathic pain signaling but also for the disease maintenance. Insights gained from this study are clinically relevant in the development of DLK inhibitors for pain management.
Scientific Focus Area: Neuroscience
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