Peptides encoded by 5’ untranslated regions mediate pain sensitization

Nociceptors are neurons responsible for the detection of pain producing stimuli. Persistent changes in their activity, termed plasticity, benefit survival through injury avoidance and are regulated on a translational basis. Yet, the mRNAs whose translation facilitates plasticity are unknown. Here, we apply ribosome profiling to dorsal root ganglion and identify a small number of transcripts that are selectively translated in response to plasticity mediators. Among them are Arc and Fos, genes implicated in episodic learning in the brain. We demonstrate that the ribosomal S6 kinase 1 is responsible for their production in nociceptors. Blocking S6 driven translation also reduces pain associated behavioral responses in vivo. In addition to translation of coding regions of mRNA, we detect pervasive ribosome occupancy in 5’ untranslated regions. We find that peptides encoded by open reading frames in the 5’ untranslated regions of Calca and Egr2 increase neuronal excitability in vitro and are sufficient to induce pain-like behaviors in vivo. Together, our findings uncover new targets of translational control that drive changes in plasticity and suggest new mechanisms for targeted pain therapeutics that disrupt pain signaling. We applied ribosome profiling to DRG neurons in culture in response to NGF/IL-6 treatment