Investigating the Role of CircRNAs in Pain and Nocieptive Sensitization

University Of New Mexico Health Scis Ctr, Albuquerque NM

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Abstract

Chronic pain affects over 50 million Americans and remains a leading contributor to opioid use. The dorsal root ganglion (DRG) plays a central role in pain signal transmission, yet the molecular mechanisms underlying pain sensitization in the DRG are not fully understood. Circular RNAs (circRNAs) are stable RNA molecules enriched in the nervous system that regulate gene expression post-transcriptionally. Our preliminary data identify a circRNA, circNTRK2, derived from the gene encoding the TrkB receptor, which is significantly downregulated in the DRG following repeated opioid exposure. CircNTRK2 directly binds to the 3' untranslated region of brain-derived neurotrophic factor (BDNF) mRNA, a key molecule involved in inflammation and pain sensitization. This project will define the regulatory function of circRNAs in DRG neurons and evaluate their role in chronic pain. We hypothesize that circNTRK2 represses BDNF expression under normal conditions, and that loss of circNTRK2 contributes to heightened pain sensitivity. We will (1) map circNTRK2 and pain-linked circRNA expression in human DRG tissue using sequencing and spatial transcriptomics, (2) define how circNTRK2 regulates BDNF mRNA stability and translation in vitro, and (3) determine circNTRK2’s functional role in vivo using antisense oligonucleotides and animal models of opioid-induced and inflammatory pain. The study integrates transcriptomics, RNA–RNA interaction assays, and behavioral models to investigate a new post-transcriptional mechanism in pain. Outcomes include a publicly available circRNA atlas of human DRG, novel mechanistic insights into circRNA function in pain, and preclinical validation of a new non-opioid therapeutic target. This work addresses urgent public health needs by supporting the development of RNA-based strategies for chronic pain.