Post-transcriptional Controls in Nociceptive Signaling

Chronic pain is a condition wherein pain continues beyond the completion of the healing process. It is a debilitating condition that diminishes quality of life and is highly prevalent. Persistent pain is characterized by nociceptor plasticity. Dorsal root ganglion (DRG) neurons are responsible for generating nociceptive signals and undergo plasticity changes following injury. These changes are intimately linked to persistent pain. Translational regulation of mRNA permeates pain plasticity. Yet, the identity of translationally regulated mRNA that mediates plasticity is unknown. In this study, we used ribosome profiling to determine the protein landscape of sensory neurons after a brief exposure to the inflammatory mediators, NGF and IL-6. We observed preferential translation of a variety of transcripts. We focused on two immediate early genes, Arc and c-Fos that play a role in neuronal plasticity. These proteins have two very distinct functions: Arc regulates neuroinflammation while c-Fos regulates neuronal excitability. We also observed ribosomal occupancy on long non- coding RNAs as well as uORF utilization in certain mRNA transcripts. Among the various uORF containing transcripts, we identified a novel peptide generated from a uORF present in the 5ˊUTR of Calca mRNA. This short peptide generated from Calca is responsible for nociceptor sensitization via Gq signaling. Finally, we also identified that the 3’UTRs of preferentially translated mRNA contained a U-rich element for a RNA- binding protein called HuR. This protein contributes to nociceptor firing and mechanical hypersensitivity in mice. Our work provides insights into new key players that govern neuronal functions.