Chronic pain is a pervasive and devastating condition. Translational control is a dominant theme in synaptic plasticity and plays a key role in pain plasticity, in particular the plasticity of peripheral nociceptors. Messenger RNA (mRNA) is subject to dynamic regulation by signaling pathways implicated in plasticity such as the integrated stress response (ISR) and mTOR. Yet, the identity of the mRNAs in nociceptors subjected to regulated translation during plasticity events is virtually unknown. Here, we use an exciting new genomics method termed ribosome profiling to gain genome-wide insight into translation control events in DRG neurons. Our preliminary studies reveal a rapid induction of translation of a specific subset of mRNAs that are known to be involved in neuronal plasticity in response to cytokine treatment of DRG neurons. Among them is the immediate early gene Arc. We identify S6K as required for activity dependent translation of Arc. A chemical inhibitor of S6K attenuates mechanical hypersensitivity in a model of inflammatory pain. Additionally, our preliminary data also indicate evidence for translation of a specific 5? untranslated region (UTR) reading frame encoded by Calca/CGRP. The resulting peptide is able to promote pain amplification in vivo. In the first aim of this proposal, we will comprehensively characterize translation regulation in DRG neurons in response to cytokines with a focus on underlying mechanisms and targets of interest. We examine the function of a specific uORF with electrophysiology and pharmacology. In the second aim, we examine the effects of methylglyoxal (MGO) on translation. MGO is associated with diabetic neuropathy as well as discogenic neuropathies and our preliminary data indicate that its pain promoting effects depend on induction of the ISR. Interestingly, the ISR induces translation of uORFs suggesting this non-canonical form of translation as a new theme in neuropathic pain. We will probe the effects of MGO on translational control and determine if blocking the ISR is a viable option for neuropathic pain. Our experiments demonstrate the tremendous potential of a transformative genomics tool that enables new views on pain plasticity with astonishing molecular clarity.
Poorly managed pain creates an enormous burden on our healthcare system and produces tremendous human suffering. This research program focuses on mechanisms that promote chronic pain to gain a better understanding of disease mechanisms for the eventual development of more effective therapeutics. We plan to utilize cutting edge, unbiased methods for the detection of novel pain plasticity signaling pathways that we anticipate will have a broad impact on the neurosciences.
