Semin Neurol 2005; 25(3): 278-289
DOI: 10.1055/s-2005-917664
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Tropical Marine Neurotoxins: Venoms to Drugs

Michael R. Watters1
  • 1Professor of Medicine, Division of Neurology, University of Hawaii, Honolulu, Hawaii
Further Information

Publication History

Publication Date:
19 September 2005 (online)


Neurotoxic venoms are common among tropical marine creatures, which have specialized apparatuses for delivery of the venoms. These include jellyfish and anemones, venomous cone snails, venomous fish, stingrays, sea snakes, and venomous octopuses. Numerous toxic neuropeptides are found within these venoms, and some can discriminate between closely related intracellular targets, a characteristic that makes them useful to define cation channels and attractive for drug development. A synthetic derivative of an omega-conotoxin is now available, representing a new class of analgesics. In general, toxic marine venoms contain proteins that are heat labile, providing opportunity for therapeutic intervention following envenomation, while ingestible seafood toxins are thermostable toxins. Ingestible toxins found in the tropics include those associated with reef fish, pufferfish, and some shellfish, which serve as food-chain vectors for toxins produced by marine microorganisms.


  • 1 Watters M R, Cannard K R. Marine neurotoxins. In: Chopra JS, Sawhney IMS Neurology in Tropics. New Delhi; Churchill Livingstone 1999: 45-68
  • 2 Tomchik R S, Russell M R, Szmant A M, Black N. Clinical perspectives on sunbather's eruption, also known as “sea lice.”  JAMA. 1993;  269 1669-1672
  • 3 Watters M R, Yanagihara A A. Marine neurotoxins: envenomations and contact toxins. In: Watters MR (dir) Marine Toxins, AAN Syllabus 5BS.003. St. Paul, MN; American Academy of Neurology 2003: 1-27
  • 4 Hodgson W C. Pharmacological action of Australian venoms.  Clin Exp Pharmacol Physiol. 1997;  24 10-17
  • 5 Watters M R, Stommel E W. Marine toxins: envenomations and contact toxins.  Curr Treat Options Neurol. 2004;  6 115-123
  • 6 Chung J J, Ratnapala L A, Cooke I M, Yanagihara A A. Partial purification and characterization of the hemolysin (CAH1) from Hawaiian box jellyfish (Carybdea alata) venom.  Toxicon. 2001;  39 981-990
  • 7 Fenner P J, Williamson J A. Worldwide deaths and severe envenomation from jellyfish stings.  Med J Aust. 1996;  165 658-661
  • 8 Edwards L, Hessinger D A. Portuguese man-of-war (Physalia physalis) venom induces calcium influx into cells by permeabilizing plasma membranes.  Toxicon. 2000;  38 1015-1028
  • 9 Fenner P, Seymour J. Irukandji jellyfish. Available at:
  • 10 Walker M JA. Coelenterate and echinoderm toxins: mechanisms and actions. In: Tu AT Handbook of Natural Toxins. Vol. 3: Marine Toxins and Venoms. New York; Marcel Dekker 1988: 280-325
  • 11 Auerbach P S. Marine envenomation. In: Auerbach PS Wilderness Medicine: Management of Wilderness and Environmental Emergencies. 3rd ed. St Louis; Mosby 1995: 1327-1374
  • 12 Ludolph A C. Sea anemone toxins. In: Spencer PS, Schaumburg HH Experimental and Clinical Neurotoxicology. 2nd ed. Oxford; Oxford University Press 2000: 1099-1100
  • 13 Norton R S. Structure and structure-function relationships of sea anemone proteins that interact with the sodium channels.  Toxicon. 1991;  29 1051-1084
  • 14 Thomas C S, Scott S A, Galanis D J et al.. Box jellyfish (Carybdea alata) in Waikiki: their influx cycle plus the analgesic effect of hot and cold packs on their stings to swimmers at the beach: a randomized, placebo-controlled, clinical trial.  Hawaii Med J. 2001;  60 100-107
  • 15 Yoshimoto C M, Yanagihara A A. Cnidarian (coelenterate) envenomations in Hawaii improve following heat application.  Trans R Soc Trop Med Hyg. 2002;  96 300-303
  • 16 Nomura J T, Sato R L, Ahern R M et al.. A randomized paired comparison trial of cutaneous treatments of acute jellyfish (Carybdea alata) stings.  Am J Emerg Med. 2002;  20 624-626
  • 17 Fenner P. Chironex fleckeri (multi-tentacled box jellyfish). Available at:
  • 18 Farr-Jones S, Miljanich G P, Nadasdi L, Ramachandran J, Basus V J. Solution structure of omega-conotoxin MVIIc, a high affinity ligand of P-type calcium channels, using 1H NMR spectroscopy and complete relaxation matrix analysis.  J Mol Biol. 1995;  248 106-124
  • 19 Fainzilber M, Hasson A, Oren R et al.. New mollusk-specific alpha-conotoxins block Aplysia neuronal acetylcholine receptors.  Biochemistry. 1994;  33 9523-9529
  • 20 Hill J M, Alewood P F, Craik D J. Three-dimensional solution structure of muconotoxin GIIIb, a specific blocker of skeletal muscle sodium channels.  Biochemistry. 1996;  35 8824-8835
  • 21 Cruz L J. Conotoxins. In: Spencer PS, Schaumburg HH Experimental and Clinical Neurotoxicology. 2nd ed. Oxford; Oxford University Press 2000: 417-419
  • 22 Auerbach P S. Clinical therapy of marine envenomation and poisoning. In: Tu AT Handbook of Natural Toxins. Vol. 3: Marine Toxins and Venoms. New York; Marcel Dekker 1988: 493-565
  • 23 Olivera B M, Cruz L J, de Santos V et al.. Neuronal calcium channel antagonists: discrimination between calcium channel subtypes using omega-conotoxin from Conus magnus venom.  Biochemistry. 1987;  26 2086-2090
  • 24 Zamponi G W. Interactions of voltage gated calcium channels with peptide toxins from spiders and snails. Presented at the Venom to Drugs International Symposium, July 2002 Heron Island, Australia;
  • 25 Olivera B M, Bandyopadhyay P K, Wilcox K S, Grzegorz B, White H S, McIntosh J M. Conus peptides, a conceptual overview of the pharmacological resource: specific issues relevant to drug development. Presented at the Venom to Drugs International Symposium, July 2002 Heron Island, Australia;
  • 26 Azimi-Zonooz A, Kawa C B, Dowell C D, Olivera B M. Autoradiographic localization of N-type VGCCs in gerbil hippocampus and failure of w-conotoxin MVIIa to attenuate neuronal injury after transient cerebral ischemia.  Brain Res. 2001;  907 61-70
  • 27 Berman R F, Verweij B H, Muizelaar J P. Neurobehavioral protection by the neuronal calcium channel blocker Ziconotide in a model of traumatic diffuse brain injury in rats.  J Neurosurg. 2000;  93 821-828
  • 28 Watters M R. Update in pain, conotoxins as analgesics: ziconotide. In: Watters MR (dir) Update in Neurology Western Winter Meeting, AAN Syllabus. St. Paul, MN; American Academy of Neurology 2004: 1-13
  • 29 Newcomb R, Abbruscato T J, Singh T et al.. Bioavailability of ziconotide in brain: influx from blood, stability, and diffusion.  Peptides. 2000;  21 491-501
  • 30 Brammar W J. Voltage-gated calcium channels. In: Conley EC, Brammer WJ Ion Channel Facts Book. Vol. 4: Voltage-Gated Channels. London; Academic Press 1999: 22-153
  • 31 Catterall W A. Structure and function of neuronal calcium channels and their role in neurotransmitter release.  Cell Calcium. 1998;  24 307-323
  • 32 Cox B. Calcium channel blockers and pain therapy.  Curr Rev Pain. 2000;  4 488-498
  • 33 Santicioli P, Del Bianco E, Tramontana M et al.. Release of calcitonin gene-related peptide-like immunoreactivity induced by electrical field stimulation from rat spinal afferents is mediated by conotoxin-sensitive calcium channels in rat sensory neurons.  Neurosci Lett. 1992;  136 161-164
  • 34 Holz G G, Dunlap K, Kream R M. Characterization of the electrically evoked release of substance P from dorsal root ganglion neurons: methods and dihydropyridine sensitivity.  J Neurosci. 1988;  8 463-471
  • 35 Malmberg A B, Yaksh T L. Voltage-sensitive calcium channels in spinal nociceptive processing: blockage of N- and P-type channels inhibits formalin-induced nociception.  J Neurosci. 1994;  14 4882-4890
  • 36 Jain K K. An evaluation of intrathecal ziconotide for the treatment of chronic pain.  Expert Opin Investig Drugs. 2000;  9 2403-2410
  • 37 Wermeling D, Drass M, Ellis D et al.. Pharmacokinetics and pharmacodynamics of intrathecal ziconotide in chronic pain patients.  J Clin Pharmacol. 2003;  43 624-636
  • 38 Smith M T, Cabot P J, Ross F B, Robertson A D, Lewis R J. The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices.  Pain. 2002;  96 119-127
  • 39 Wang Y X, Pettus M, Gao D, Phillips C, Bowersox S S. Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain.  Pain. 2000;  84 151-158
  • 40 Wang Y X, Bowersox S S. Analgesic properties of ziconotide, a selective blocker of N-type neuronal calcium channels.  CNS Drug Rev. 2000;  6 1-20
  • 41 Mathur V S. Ziconotide: a new pharmacological class of drug for the management of pain.  Semin Anesth Periop Med Pain. 2000;  19 67-75
  • 42 Staats P S, Yearwood T, Charapata S G et al.. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial.  JAMA. 2004;  291 63-70
  • 43 Bowersox S, Tich N, Mayo M et al.. SNX-111 antinociceptive agent N-type voltage-sensitive calcium channel blocker.  Drugs Future. 1998;  23 152-160
  • 44 Penn R D, Paice J A. Adverse effects associated with the intrathecal administration of ziconotide.  Pain. 2000;  85 291-296
  • 45 Wang Y X, Gao D, Pettus M, Phillips C, Bowersox S S. Interactions of intrathecally administered ziconotide, a selective blocker of neuronal N-type voltage-sensitive calcium channels, with morphine on nociception in rats.  Pain. 2000;  84 271-281
  • 46 Mathur V, McGuire D, Bowersox S et al.. Neuronal N-type calcium channels: new prospect in pain therapy.  Pharm News. 1998;  5 25-29
  • 47 Brown C K, Shepherd S M. Marine trauma, envenomations, and intoxications.  Emerg Med Clin North Am. 1992;  10 385-408
  • 48 Maretic Z. Fish venoms. In: Tu AT Handbook of Natural Toxins. Vol. 3: Marine Toxins and Venoms. New York; Marcel Dekker 1988: 445-476
  • 49 Auerbach P S. Marine envenomations.  N Engl J Med. 1991;  325 486-493
  • 50 Kizer K W, McKinney H E, Auerbach P S. Scorpaenidae envenomation: a five-year poison control experience.  JAMA. 1985;  253 807-810
  • 51 Wasserman G S, Johnston R M. Poisoning from lionfish sting.  Vet Hum Toxicol. 1979;  21 344-345
  • 52 Tu A T. Sea snakes and their venoms. In: Tu AT Handbook of Natural Toxins. Vol. 3: Marine Toxins and Venoms. New York; Marcel Dekker 1988: 379-344
  • 53 Ludolph A C. Erabutoxins. In Spencer PS, Schaumburg HH Experimental and Clinical Neurotoxicology. 2nd ed. Oxford; Oxford University Press 2000: 534-535
  • 54 Burne J A, Webster M E. The action of erabutoxins “b” on spontaneous and glutamate-induced cortical activity.  Life Sci. 1977;  20 2023-2028
  • 55 Taub A M, Elliott W B. Some effects of snake venoms on mitochondria.  Toxicon. 1964;  104 87-92
  • 56 Baxter E H, Gallichio H A. Cross-neutralization by tiger snakes (Notechis scutatus) antivenin and sea snake (Enhydrina schistosa) antivenin against several sea snake venoms.  Toxicon. 1974;  12 273-278
  • 57 Tu A T, Gulde G. Sea snake bite.  Clin Dermatol. 1987;  5 118-126
  • 58 Narahashi T. Tetrodotoxin. In: Spencer PS, Schaumburg HH Experimental and Clinical Neurotoxicology. 2nd ed. Oxford; Oxford University Press 2000: 1162-1164
  • 59 Narahashi T. Mechanism of tetrodotoxin and saxitoxin action. In: Tu AT Handbook of Natural Toxins. Vol. 3: Marine Toxins and Venoms. New York; Marcel Dekker 1988: 185-210
  • 60 Watters M R. Organic neurotoxins in seafoods.  Clin Neurol Neurosurg. 1995;  97 119-124
  • 61 Fuhrman F A. Tetrodotoxin, tarichtoxin, and chiriquitoxin: historical perspectives.  Ann N Y Acad Sci. 1986;  479 1-14
  • 62 Kaempfer E. History of Japan. Vol. 1. Scheuchzer JG, trans. London; Johann Gaspar Scheuchzer; 1727
  • 63 Mills A R, Passmore R. Pelagic paralysis.  Lancet. 1988;  1 161-164
  • 64 Halstead B W. Poisonous and Venomous Marine Animals of the World. Princeton; Darwin Press 1988
  • 65 Stommel E W, Watters M R. Marine neurotoxins: ingestible toxins.  Curr Treat Options Neurol. 2004;  6 105-114
  • 66 Watters M R. Geographic medicine: the hazards of eating seafood. In: Marra C (dir) Infections of the Nervous System, AAN Syllabus 7FC.006. St. Paul, MN; American Academy of Neurology 1998: 159-171
  • 67 DiNubile M J, Hokama Y. The ciguatera poisoning syndrome from farm-raised salmon.  Ann Intern Med. 1995;  122 113-114
  • 68 Hokama Y. Simplified solid-phase immonobead assay for detection of ciguatoxin and related polyethers.  J Clin Lab Anal. 1990;  4 213-217
  • 69 Kodama A M, Hokama Y, Yasumoto T et al.. Clinical and laboratory findings implicating palytoxin as cause of cituatera poisoning due to Decapterus macrosoma (mackerel).  Toxicon. 1989;  27 1051-1053
  • 70 Hirata Y. Chemistry and pharmacology of palytoxin. In: Tu AT Handbook of Natural Toxins. Vol. 3: Marine Toxins and Venoms. New York; Marcel Dekker 1988: 242-258
  • 71 Withers N W. Ciguatera fish toxins and poisonings. In: Tu AT Handbook of Natural Toxins. Vol. 3: Marine Toxins and Venoms. New York; Marcel Dekker 1988: 31-61
  • 72 Pearn J. Neurology of ciguatera.  J Neurol Neurosurg Psychiatry. 2001;  70 4-8
  • 73 Bagnis R, Kuberski T, Lamgier S. Clinical observations on 3,009 cases of ciguatera (fish poisoning) in the South Pacific.  Am J Trop Med Hyg. 1979;  28 1067-1073
  • 74 Schnorf H, Taurarii M, Cundy T. Ciguatera fish poisoning: a double-blind randomized trial of mannitol therapy.  Neurology. 2002;  58 873-880
  • 75 Underman A E, Leedom J M. Fish and shellfish poisoning.  Curr Clin Top Infect Dis. 1993;  13 203-225
  • 76 Watters M R. Organic neurotoxins in seafoods. In: Rose FC Recent Advances in Tropical Neurology. Amsterdam; Elsevier Science 1995: 299-312
  • 77 Taylor T J, Smith N C, Langford M J et al.. Effect of palytoxin on endothelium-dependent and -independent relaxation in rat aortic rings.  J Appl Toxicol. 1995;  15 5-12
  • 78 Stommel E W, Parsonnet J, Jenkyn L R. Polymyositis after ciguatera toxin exposure.  Arch Neurol. 1991;  48 874-877
  • 79 Stommel E W, Jenkyn L R, Parsonnet J. Another case of polymyositis after ciguatera toxin exposure.  Arch Neurol. 1993;  50 571
  • 80 Cameron J, Flowers A E, Capra M F. Effects of ciguatoxin on nerve excitability in rats (part I).  J Neurol Sci. 1991;  101 87-92
  • 81 Benoit E, Juzans P, Legrand A M, Molgo J. Nodal swelling produced by ciguatoxin-induces selective activation of sodium channels in myelinated nerve fibers.  Neuroscience. 1996;  71 1121-1131
  • 82 Mattei C, Dechraoui M Y, Molgo J et al.. Neurotoxins targeting receptor site 5 of voltage-dependent sodium channels increase the nodal volume of myelinated axons.  J Neurosci Res. 1999;  55 666-673
  • 83 Allsop J L, Martini L, Lebris H et al.. Neurologic manifestations of ciguatera: 3 cases with a neurophysiologic study and examination of one nerve biopsy.  Rev Neurol (Paris). 1986;  142 590-597
  • 84 Cameron J, Flowers A E, Capra M R. Electrophysiological studies on ciguatera poisoning in man (part II).  J Neurol Sci. 1991;  101 93-97
  • 85 Palafox N A, Jain L G, Pinano A Z et al.. Successful treatment of ciguatera fish poisoning with intravenous mannitol.  JAMA. 1988;  259 2740-2742
  • 86 Pearn J, Lewis R. Ciguatera and mannitol: experience with a new treatment regimen.  Med J Aust. 1989;  151 77-80
  • 87 Legrand A M, Galonnier M, Bagis R. Studies on the mode of action of ciguateric toxins.  Toxicon. 1982;  20 311-315

Michael R WattersM.D. 

Department of Medicine, John A. Burns School of Medicine

1356 Lusitana Street, 7th Floor

Honolulu, HI 96813