Roger de la Halle/Gallo ImagesThe black mamba snake: an ugly critter with a wonderful giftAt first you might feel a slight sting as the fangs enter. Then, a tingling will spread throughout your limbs. But within minutes your central nervous system will start shutting down, culminating in convulsions, paralysis, and a suffocating death. The venom of the black mamba snake, one of the world’s deadliest poisons administered by one of the world’s deadliest reptiles, can kill you within half an hour. Untreated bites have a mortality rate of 100%.
Hidden in the grim cocktail the snake carries, though, are a couple of proteins with a remarkably different effect. Research published this week in Nature has revealed two molecules in mamba venom that can eliminate pain with as much potency as morphine, suggesting an unusual new source for painkillers.
Sylvie Diochot, an engineer at France’s Institute of Pharmocologie Moleculaire and Cellulaire and first author of the paper, has always had a yen for the venomous. Fascinated by the destructive power of black widow bites, she studied venomous arthropods and was on familiar terms with her specimens. “Sometimes, I had several spiders and scorpions at home, in breeding, but I have children at home, so I prefer to observe them in nature (photos), or sometimes in our laboratory,” she wrote in an e-mail. Her research involved purifying the toxin molecules that make venom so deadly and then applying them to neurons and other cells to study how they send the body into catastrophic failure.
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The conclusion that venom investigators like Diochot have reached is that the things that make animal venoms so deadly are often proteins that work by jamming open or closed the channels that let ions flow across the membranes of neurons. Chemical cross-chatter into and out of the cells is what allows neurons to send messages to the brain and elsewhere. Disrupt that communications feed and the whole system can come crashing down.
But not all the information neurons transmit is good. Pain, after all, is a neuronal signal too. Sometimes it’s a very helpful one, as when it alerts you that you might want to remove your hand from the hot stove you just touched. Sometimes it’s decidedly unhelpful; what good, exactly, is a migraine headache, chronic back pain, postsurgical pain? In cases like those, shutting down selected neuronal signals would be a very good thing. In the 1990s, researchers found a protein in the venom of the sea-dwelling cone snail that could do just that, disturbing the function of calcium ion channels such that pain signals never made it to the brain. A synthetic version of the molecule they extracted, ziconotide, is now being used to treat patients with severe chronic pain, a success story that inspires venom researchers today.
To see whether they could find anything in various venoms that had a similar effect on another set of pain-related channels, Diochot — along with her lab chief, neurobiologist Eric Lingueglia, and other collaborators — borrowed and bought more than 40 venoms from scorpions, spiders, sea anemones and snakes. Each was carefully separated into its component molecules, which were then poured on frog cells. What they were looking for was whether the molecules affected what are known as acid-sensing ion channels — which can play a key role in nociception, or the transmission of pain signals. Quickly, they saw that particular black mamba proteins, dubbed mambalgin-1 and -2, did block the ion channels in frog cells, at least in a petri dish. They had a similar effect on human cells — in a dish as well.
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The next step was to try the preparation in a living creature, in this case mice. Since mice can’t tell you if something hurts — never mind how much — the researchers conducted two standard pain experiments. After administering mambalgin-1 and -2 to their subjects, they dipped the paws of some of the animals in hot water; in others they injected the paws with substances that briefly cause pain. Mice respond to such stimuli by withdrawing their paws from the water and licking the pricked paws; how quickly they withdraw and how many times they lick are measures of how much pain they feel.
On both of these yardsticks, mice that had received mambalgin appeared to feel much less pain than those that had received none. The magnitude of the reduction is similar to the reduction that occurs when mice are given morphine. Although mambalgin got less effective the longer the mice were exposed it, tolerance did not develop nearly as fast as with morphine, and the mice did not have difficulty breathing, as they did when on morphine.
It will take a lot of work — and a lot of toxicity testing — before this particular venom extract or synthetic compounds like it are approved for human use, but even if it is, don’t expect it to replace aspirin or ibuprofen, or even morphine in most circumstances. Like ziconotide before it, it may need to be injected into the spine or elsewhere to have best effect, which means it may be primarily useful in the alleviation of certain types of chronic severe pain for which there is no other treatment. “For neuropathic pain, which is associated with problems in the nervous system, and for people with very severe pain, like in very advanced cancer, morphine is not very efficient,” says Lingueglia. “For these people, we have only a few molecules that can be active on their pain.”
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That’s a very important niche — both in a humanitarian and economic sense — and for that reason, acid-sensing ion channels have been on drug companies’ radars for a while, says William Catterall, a pharmacologist at University of Washington. Mambalgin’s structure has been patented, and one of the paper’s authors is on the scientific board of Theralpha, a biotechnology company that is looking to develop the protein for use in humans.
Of less interest to pharmacologists than herpetologists is why such a deadly venom contains such a potent painkiller in the first place. What could be the advantage — either to the snake or to the victim? “This is a very good question,” says Lingueglia with a laugh. “It’s very surprising, because when the snake bites you, you are dead in a very short time. I don’t think analgesic peptides are of interest to the snake.”