{"doi":"10.1021/acsptsci.1c00072","title":"Pharmacological Inhibition of the Voltage-Gated Sodium Channel Na<sub>V</sub>1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome","abstract":"The human nociceptor-specific voltage-gated sodium channel 1.7 (hNaV1.7) is critical for sensing various types of somatic pain, but it appears not to play a primary role in acute visceral pain. However, its role in chronic visceral pain remains to be determined. We used assay-guided fractionation to isolate a novel hNaV1.7 inhibitor, Tsp1a, from tarantula venom. Tsp1a is 28-residue peptide that potently inhibits hNaV1.7 (IC50 = 10 nM), with greater than 100-fold selectivity over hNaV1.3–hNaV1.6, 45-fold selectivity over hNaV1.1, and 24-fold selectivity over hNaV1.2. Tsp1a is a gating modifier that inhibits NaV1.7 by inducing a hyperpolarizing shift in the voltage-dependence of channel inactivation and slowing recovery from fast inactivation. NMR studies revealed that Tsp1a adopts a classical knottin fold, and like many knottin peptides, it is exceptionally stable in human serum. Remarkably, intracolonic administration of Tsp1a completely reversed chronic visceral hypersensitivity in a mouse model of irritable bowel syndrome. The ability of Tsp1a to reduce visceral hypersensitivity in a model of irritable bowel syndrome suggests that pharmacological inhibition of hNaV1.7 at peripheral sensory nerve endings might be a viable approach for eliciting analgesia in patients suffering from chronic visceral pain.","journal":"ACS Pharmacology & Translational Science","year":2021,"id":172573,"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":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9626,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":695242,"name":"Joel Castro","orcid":"0000-0002-5781-2224","position":1,"is_corresponding":false},{"id":708861,"name":"Linda V. Blomster","orcid":"0000-0002-7611-9740","position":2,"is_corresponding":false},{"id":708862,"name":"Akello J. Agwa","orcid":"0000-0001-9295-5071","position":3,"is_corresponding":false},{"id":708863,"name":"Jessica Maddern","orcid":"0000-0002-4857-7162","position":4,"is_corresponding":false},{"id":709499,"name":"Gudrun Schober","orcid":null,"position":5,"is_corresponding":false},{"id":708864,"name":"Volker Herzig","orcid":"0000-0003-2514-3983","position":6,"is_corresponding":false},{"id":402819,"name":"Chun Yuen Chow","orcid":"0000-0003-2861-5843","position":7,"is_corresponding":false},{"id":708865,"name":"Fernanda C. Cardoso","orcid":"0000-0002-0068-9974","position":8,"is_corresponding":false},{"id":280688,"name":"Paula Demétrio De Souza França","orcid":"0000-0003-4316-8834","position":9,"is_corresponding":false},{"id":402818,"name":"Junior Gonzales","orcid":"0000-0002-2266-7565","position":10,"is_corresponding":false},{"id":339298,"name":"Christina I. Schroeder","orcid":"0000-0002-6737-6374","position":11,"is_corresponding":false},{"id":709500,"name":"Steffen Esche","orcid":null,"position":12,"is_corresponding":false},{"id":245644,"name":"Thomas Reiner","orcid":"0000-0002-7819-5480","position":13,"is_corresponding":false},{"id":501070,"name":"Stuart M. Brierley","orcid":"0000-0002-2527-2905","position":14,"is_corresponding":false},{"id":402821,"name":"Glenn F. King","orcid":"0000-0002-2308-2200","position":15,"is_corresponding":false},{"id":708860,"name":"Yan Jiang","orcid":"0000-0001-5277-804X","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-18T23:46:41.424716Z","pmid":"34423271","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":[]}