Retrospectacle: A Neuroscience Blog

Cone snail shells are beautiful, but their venom is a potent cocktail used to paralyze passing fish. The venom is a witch’s brew of hundreds of novel compounds, many more than are found in snake venom (which has been used by science extensively as well). One compound in particular is a pain killer many times more effective than morphine.

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The venom apparatus consists of a muscular venom bulb which pushes venom from a gland down a long duct to a chitinous tooth (the pink thing). The tooth is like a little barbed harpoon, which becomes soaked in venom and jabs into prey. Venom is quickly injected. There is no antivenom.

The discovery of this venom is not really new: about 25 years ago, a scientist at the University of Utah, Phillipine-born Baldomera Olivera, isolated the molecule that had the painkilling properties in humans. It took a quarter of a century to produce a synthetic version of the compound, which serves as the basis of the new drug Prialt (ziconotide).

Prialt is designed to treat the most serious, persistent pain which often accompanies conditions like cancer; specifically it is aimed at treating patients who have become resistant tolerant to morphine therapy. Prialt is 1,000 more potent than morphine, but surprisingly, it is not addictive.

Prialt blocks N-type calcium channels which play a role in the transmission of pain, and mimics the action of the w-conotoxin found in the cone snail venom (see chart below for the known neurotoxic peptides in the venom, and their actions. It is designed to be delivered directly into the cerebrospinal fluid by means of a small pump.

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An interesting side note: cone snails have the world’s fasting mutating genes. The genes which encode the snail’s venom mutate at a rate that is 5 times faster than the highest mutation rate known in mammals. It is hypothesized that this rapid mutation rate allowed for the development of diverse venomous compounds which target several specific ion channels and receptors.

How is the venom, uh, collected from the snail? In snakes and other venomous creatures, this process of getting the venom is called “milking.” In the cone snail, the venom can either be extracted from the venom gland after the snail is dead or while the snail is alive. As Dr. Bingham (a collaborator with the initial discoverer of the venom) from Clarkson University said,

“The problem with the first way is that there are many compounds in the snails’ venom glands that are not actually injected into prey to paralyze and kill it. So you must sift through thousands of compounds that are unlikely to be useful. The problem with the second way is that while it is far more efficient, it is not easy to milk a highly poisonous snail.”

One last thought: I haven’t been able to determine whether the pain-relieving qualities of the venom, which are potent in humans, have the same effect in the snails prey (fish and mollusks). Initially, it seems intriguing that venom would have evolved to so, uh, merciful. However reducing pain in the snail’s prey may have had the effect of reducing struggling and making it more likely the snail will get to eat the prey before another fish does. This might really come in handy if the pain relief was instantaneous while the paralysis neuropeptide was a bit slower acting. The prey may be discouraged from initially reacting to the pain of the sting, allowing time for the crucial paralysis effects to occur. (Just a guess….)

Comments

  1. #1 Jeb, FCD
    August 9, 2007

    Reminds me of Jurassic Park 2(?). One of the defensive weapons was a dart with enhanced aconotoxin that worked faster than the nerve conduction velocity so if you shot yourself, you’d be dead before feeling the dart.

  2. #2 PhysioProf
    August 9, 2007

    Several Points:

    (1) Prialt actually *is* the w-conotoxin MVIIA peptide that is found in the venom of Conus magus. It’s just that it’s chemically sythesized, rather than purified from venom.

    (2) It’s function in the venom is to block the presynaptic calcium channels at the neuromuscular synapses of the fish that Conus magus preys on. This paralyzes the fish.

    (3) The reason it is effective at treating intractable pain with few side effects is that it is applied intrathecally (in the CSF of the spinal cord), and the only calcium channels in the spinal cord that are sensitive to MVIIA are those in the central presynaptic terminals of pain-sensing neurons.

  3. #3 Shelley
    August 9, 2007

    PhysioProf: Thanks much for clearing that up! I was wondering what the effects on the snails prey were. Although it sounded like the side effects are actually pretty intense.

    The most frequently reported adverse events (=25%) in the 1254 patients (662 patient years) in clinical trials were dizziness, nausea, confusion, headache, somnolence, nystagmus, asthenia, and pain. Serious adverse events and discontinuation of PRIALT for adverse events are less frequent when the drug is slowly titrated over 21 days, than with a faster titration schedule. (http://www.rxlist.com/cgi/generic/ziconotide_ad.htm)

    Although maybe in the scheme of things, these aren’t that bad really.

  4. #4 Size
    August 9, 2007

    This is really interesting stuff. Thanks for this write-up.

  5. #5 PhysioProf
    August 9, 2007

    “few side effects”

    Yeah, that is a bit of an exaggeration. I am not a physician, but my understanding is that Prialt is only considered as a last resort, after all other pain relief regimes have failed.

  6. #6 Chromosome Crawl
    August 9, 2007

    Early phase (I, II) studies for this drug had dosage titration issues that caused psychotic reactions in test subjects. VERY vivid hallucinations and paranoia. Once the dosage was lowered things smoothed out for later phase trials & marketing purposes.

    Maybe the prey hallucinates while it is dying?

  7. #7 Luna_the_cat
    August 10, 2007

    Cone snails have fascinated me for years. As I understand it, though, one of the frustrating things about sifting through their venom for useful molecules, has been that many properties of the venom appear to be the result of interaction of multiple components — and what is worse, the components of snail venom change with how it is obtained (i.e. dissecting a dead snail, getting them to “dart” a prey fish and recovering the venom from the fish, or otherwise forcing the snail to express venom). It’s also like spider-silk, in a way: there also seem to be some post-translational modifications of crucial proteins, so simply duplicating gene products won’t do it for you. (If I’m wrong about any of this, I would love more information, hint, hint….)

    Biochemically speaking, I think cone snails are just about the most fascinating critters on the planet. Shame so many of them are killed to sell shells to tropical tourists; I understand a lot of wild populations are either gone or threatened, now.

  8. #9 Luna_the_cat
    August 13, 2007

    …all the info on that site is fairly basic, though, as far as I can tell. And I wish they didn’t encourage people to collect them!

  9. #10 T.L.Wilson
    May 11, 2011

    Many Questions:
    1) Given the number of compounds present does CONUS administer broad spectrum with each strike.
    2) Is each strike a custom mix given the type of prey and it’s physical attributes or bio-electric output, ( is this mechanism auto-program or are there sensory criteria that deterimine which cocktail to mix.
    3) What are the sensory abilities of CONUS,(has any one given him an eye test?)
    4) Nature rarely wastes it’s defense ability, does Conus have a standard battery, 1 for hunting, 1 for self defense?

  10. #11 oscar
    May 24, 2011

    la información, es realmente interesante; me gustaría tener mayor información al respecto, pues recientemente encontre un articulo sobre el tema del veneno de caracol conico y me gustaría ampliar mi conocimiento sobre el tema; ademas sobre sus aplicaciones en la medicina moderna.