Long-lasting analgesia by antisense-mediated switching of TRPV1 isoforms

Raw Data for "Long-lasting analgesia by antisense-mediated switching of TRPV1 isoforms" Abstract:Chronic pain affects approximately 20-25% of the global population, yet existing treatments either offer insufficient relief or pose significant risks including addiction. Transient receptor potential vanilloid-1 (TRPV1) is fundamental to pain transmission. Conversely, its splicing isoform TRPV1b, lacking exon 7, is intrinsically insensitive to noxious stimuli. Here, we used splice-switching strategy to suppress TRPV1 while simultaneously increasing TRPV1b expression. Stepwise screening of 172 antisense oligonucleotides (ASOs) identified a bipartite ASO that efficiently promoted TRPV1 exon 7 skipping in cultured cells and mouse tissues. Intracerebroventricular administration of this ASO elevated basal pain thresholds and produced long-term analgesia across neuropathic, inflammatory, and cancer pain models in mice without inducing overt toxicity or motor deficits. Mechanistically, TRPV1b forms hetero-oligomers with full-length TRPV1, exerting a dominant-negative effect that attenuates agonist-evoked Ca²⁺ influx and channel activation. Collectively, these findings demonstrate that ASO-directed splicing modulation can successfully bypass classical on-target toxicities, introducing a novel paradigm of target-specific pre-mRNA reprogramming for chronic pain intervention. Keywords: chronic pain; nociception; TRPV1; TRPV1b; antisense oligonucleotide; RNA splicing; exon skipping; analgesia. Data Structure and Content: The dataset is organized into 11 primary folders corresponding to Figure 1, 2, 5, and S1-8. Each folder contains original uncropped RT-PCR and Western blot images. Experimental Conditions: For detailed experimental protocols associated with these images, please refer to the "STAR methods" section of the main manuscript.