{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T01:19:14Z","timestamp":1789953554628,"version":"4.0.1"},"reference-count":59,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2017,8,30]],"date-time":"2017-08-30T00:00:00Z","timestamp":1504051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["ZI1172\/3-1"],"award-info":[{"award-number":["ZI1172\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["ZI1172\/2-1"],"award-info":[{"award-number":["ZI1172\/2-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Ciguatoxins (CTXs) are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel activator toxins, the etiology of many of its neurosensory symptoms remains unresolved. We recently described that local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals. In this study, we used mouse and rat skin preparations and enzyme-linked immunosorbent assays (ELISA) to study the molecular mechanism by which P-CTX-1 induces CGRP release. We show that P-CTX-1 induces CGRP release more effectively in mouse as compared to rat skin, exhibiting EC50 concentrations in the low nanomolar range. P-CTX-1-induced CGRP release from skin is dependent on extracellular calcium and sodium, but independent from the activation of various thermosensory transient receptor potential (TRP) ion channels. In contrast, lidocaine and tetrodotoxin (TTX) reduce CGRP release by 53\u201375%, with the remaining fraction involving L-type and T-type voltage-gated calcium channels (VGCC). Using transgenic mice, we revealed that the TTX-resistant voltage-gated sodium channel (VGSC) NaV1.9, but not NaV1.8 or NaV1.7 alone and the combined activation of the TTX-sensitive VGSC subtypes NaV1.7 and NaV1.1 carry the largest part of the P-CTX-1-caused CGRP release of 42% and 34%, respectively. Given the contribution of CGRP to nociceptive and itch sensing pathways, our findings contribute to a better understanding of sensory symptoms of acute and chronic ciguatera that may help in the identification of potential therapeutics.<\/jats:p>","DOI":"10.3390\/md15090269","type":"journal-article","created":{"date-parts":[[2017,8,30]],"date-time":"2017-08-30T10:40:00Z","timestamp":1504089600000},"page":"269","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Ciguatoxins Evoke Potent CGRP Release by Activation of Voltage-Gated Sodium Channel Subtypes NaV1.9, NaV1.7 and NaV1.1"],"prefix":"10.3390","volume":"15","author":[{"given":"Filip","family":"Touska","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, University Hospital Erlangen, Krankenhausstra\u00dfe 12, 91054 Erlangen, Germany"},{"name":"Department of Cellular Neurophysiology, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Sattler","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nuremberg, Universit\u00e4tsstra\u00dfe 17, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Malsch","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nuremberg, Universit\u00e4tsstra\u00dfe 17, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Lewis","sequence":"additional","affiliation":[{"name":"Institute for Molecular Biosciences, IMB Centre for Pain Research, University of Queensland, 4072 St Lucia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4367-094X","authenticated-orcid":false,"given":"Peter","family":"Reeh","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nuremberg, Universit\u00e4tsstra\u00dfe 17, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, University Hospital Erlangen, Krankenhausstra\u00dfe 12, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.toxicon.2006.07.019","article-title":"Ciguatera: Australian perspectives on a global problem","volume":"48","author":"Lewis","year":"2006","journal-title":"Toxicon"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.4269\/ajtmh.1979.28.1067","article-title":"Clinical Observations on 3009 Cases of Ciguatera (Fish Poisoning) in the South-Pacific","volume":"28","author":"Bagnis","year":"1979","journal-title":"Am. 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