{"doi":"10.1101/2023.07.16.549195","title":"Intranasal CRMP2-Ubc9 Inhibitor Regulates Na <sub>V</sub> 1.7 to Alleviate Trigeminal Neuropathic Pain","abstract":"Abstract Dysregulation of voltage-gated sodium Na V 1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that chronic pain results in part from increased SUMOylation of collapsin response mediator protein 2 (CRMP2), leading to an increased CRMP2/Na V 1.7 interaction and increased functional activity of Na V 1.7. Targeting this feed-forward regulation, we developed compound 194 , which inhibits CRMP2 SUMOylation mediated by the SUMO-conjugating enzyme Ubc9. We further demonstrated that 194 effectively reduces the functional activity of Na V 1.7 channels in dorsal root ganglia neurons and alleviated inflammatory and neuropathic pain. Here, we employed a comprehensive array of investigative approaches, encompassing biochemical, pharmacological, genetic, electrophysiological, and behavioral analyses, to assess the functional implications of Na V 1.7 regulation by CRMP2 in trigeminal ganglia (TG) neurons. We confirmed the expression of Scn9a , Dpysl2 , and UBE2I within TG neurons. Furthermore, we found an interaction between CRMP2 and Na V 1.7, with CRMP2 being SUMOylated in these sensory ganglia. Disrupting CRMP2 SUMOylation with compound 194 uncoupled the CRMP2/Na V 1.7 interaction, impeded Na V 1.7 diffusion on the plasma membrane, and subsequently diminished Na V 1.7 activity. Compound 194 also led to a reduction in TG neuron excitability. Finally, when intranasally administered to rats with chronic constriction injury of the infraorbital nerve (CCI-ION), 194 significantly decreased nociceptive behaviors. Collectively, our findings underscore the critical role of CRMP2 in regulating Na V 1.7 within TG neurons, emphasizing the importance of this indirect modulation in trigeminal neuropathic pain.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":409657,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":863583,"name":"Heather N. Allen","orcid":"0000-0003-0771-1959","position":1,"is_corresponding":false},{"id":880662,"name":"Paz Duran","orcid":"0000-0001-8729-8636","position":2,"is_corresponding":false},{"id":964288,"name":"Aida Calderón‐Rivera","orcid":"0000-0002-0129-2848","position":3,"is_corresponding":false},{"id":254848,"name":"Kimberly Gómez","orcid":"0000-0003-1867-5041","position":4,"is_corresponding":false},{"id":1040611,"name":"Upasana Kumar","orcid":"0000-0002-2350-9374","position":5,"is_corresponding":false},{"id":1041166,"name":"Rory Shields","orcid":null,"position":6,"is_corresponding":false},{"id":1067389,"name":"Rui Zeng","orcid":"0000-0003-1188-3198","position":7,"is_corresponding":false},{"id":1068005,"name":"Akshat Dwivedi","orcid":null,"position":8,"is_corresponding":false},{"id":300865,"name":"Saumya Saurabh","orcid":"0000-0002-7524-7548","position":9,"is_corresponding":false},{"id":1040613,"name":"Olga A. Korczeniewska","orcid":"0000-0001-8399-794X","position":10,"is_corresponding":false},{"id":254857,"name":"Rajesh Khanna","orcid":"0000-0002-9066-2969","position":11,"is_corresponding":false},{"id":964287,"name":"Santiago Loya‐López","orcid":"0000-0001-6207-8370","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:21:27.199694Z","pmid":"37502910","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}