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 53-75%, 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.

• MeSH
• Ciguatera Poisoning metabolism   MeSH
• Ciguatoxins chemistry   pharmacology   MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• Hyperalgesia chemically induced   MeSH
• Rats MeSH
• Humans MeSH
• Lidocaine pharmacology   MeSH
• Membrane Potentials drug effects   MeSH
• Marine Toxins pharmacology   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• NAV1.1 Voltage-Gated Sodium Channel drug effects   MeSH
• NAV1.9 Voltage-Gated Sodium Channel drug effects   MeSH
• NAV1.7 Voltage-Gated Sodium Channel drug effects   MeSH
• Calcitonin Gene-Related Peptide drug effects   MeSH
• Receptors, Calcitonin Gene-Related Peptide drug effects   MeSH
• Tetrodotoxin pharmacology   MeSH
• Calcium metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH