Pain Medicines From Under the Sea

As a child in the Philippines, Baldomero Olivera saw vendors at the local seafood market selling bushels of cone snails with their twisting and colorful shells. Fascinated by their beauty and variety, he later learned that deadly danger lurked behind their visual allure. Many of the 600 or so known cone snail species deliver poisonous venom, which in some cases kills and in other instances paralyzes prey almost instantaneously. A tiny injection of the finger-sized snail’s venom can pack a punch potent enough to kill a full-grown man.

Olivera, now a neuroscientist at the University of Utah, has devoted his laboratory career to learning how those toxins work and to searching for their possible pharmaceutical properties. As an HHMI professor he also receives support to share his passion for cone snails’ biological diversity and neurobiology with young people around the United States and in his native land.

More than 30 years ago, he passed that fascination along to J. Michael McIntosh, a young student fresh out of high school who was helping in Olivera’s lab. Today, McIntosh still occasionally collaborates with Olivera as a University of Utah research scientist. That very first summer in Olivera’s lab, McIntosh discovered a cone snail toxin that can kill people. They wanted to understand how such a tiny tincture of venom could instantly incapacitate much larger victims.

Right away, McIntosh began purifying the peptides in the venom and then tested their effects.


Prialt Paralyzes Fish
Baldomero M. Olivera describes how Prialt, a drug derived from cone snail venom, paralyzes fish by blocking calcium channels at a motor synapse.
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Prialt Blocks Pain Signaling in Mice
Hear Baldomero M. Olivera explain why Prialt does not block the mammalian motor synapse, but does block the pain pathway in the spinal cord.
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He identified a peptide that was shown by postdoctoral fellow Lynn Kerr in Doju Yoshikami’s Utah laboratory to inhibit calcium ion channels. These channels convert electrical signals into a chemical signal—in this case, a rise in calcium within the cell—that triggers neurotransmitter release. In Richard Tsien’s group at Yale University, then postdoctoral fellows Aaron Fox (now at University of Chicago) and Ed McCleskey (now an HHMI science officer) were studying the three types of calcium channels at nerve endings. McCleskey, Fox, and Tsien (now at New York University) showed, in 1987, that McIntosh’s peptide blocked only one of those channels, called the N-type calcium channel. N channels play a role in nerve–muscle transmission in fish and amphibians, so their blockade causes paralysis. Not so in mammals.

In mammals, the N-type channel was shown to be the target by which opiate receptors suppress synaptic activity of nociceptors. This set the stage to ask whether the peptide could suppress pain similarly to opiates, an effort led by George Miljanich, while at the University of Southern California and later at the biotech company Elan. When he and collaborators added the peptide to the spinal fluid of rats, it was 1,000 times more potent than opiates at suppressing pain.


Studying Cone Snails
Baldomero M. Olivera reveals why he decided to study cone snails and what he discovered about them.
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The Discovery of Prialt
Michael McIntosh describes how he discovered the drug Prialt while working as an undergraduate in Baldomero Olivera's lab.
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After two decades of effort, the resulting pharmaceutical version of the venom peptide, with the chemical name ziconotide, was approved for sale in 2004 as Prialt. It was the first new type of chronic pain medication to reach patients in many decades. Not surprisingly, because N channels are present on many types of neurons in the central nervous system besides nociceptors, Prialt can have significant side effects. It must be infused through a pump directly into a patient’s spinal fluid and it is approved only for patients who are refractory to opiates. This is a small, but terribly important, population because they are the ones who endure the most severe and most intractable pain.

That may be just the first of many medicines derived from the tiny creatures’ toxic venom. Olivera’s lab has derived three additional peptides—each with a unique mode of action—that are in clinical testing as human analgesics. He says, “We’re looking for novel pharmacology all the time.”

-- Marc Wortman
HHMI Bulletin, February 2012

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