# Profiling Translation in Nociceptor Plasticity

> **NIH NIH R01** · UNIVERSITY OF TEXAS DALLAS · 2021 · $403,530

## Abstract

Project Summary/Abstract
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.

## Key facts

- **NIH application ID:** 10256802
- **Project number:** 5R01NS114018-02
- **Recipient organization:** UNIVERSITY OF TEXAS DALLAS
- **Principal Investigator:** Zachary Campbell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $403,530
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10256802

## Citation

> US National Institutes of Health, RePORTER application 10256802, Profiling Translation in Nociceptor Plasticity (5R01NS114018-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10256802. Licensed CC0.

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