Painkilling chemicals with no side effects found in black mamba venom

By Ed Yong | October 3, 2012 1:00 pm

The black mamba has a fearful reputation, and it’s easy to see why. It can move at around 12.5 miles (20 kilometres) per hour, making it one of the world’s fastest snakes, if not the fastest. Its body can reach 4.5 metres in length, and it can lift a third of that off the ground. That would give you an almost eye-level view of the disturbingly black mouth from which it gets its name. And inside that mouth, two short fangs deliver one of the most potent and fast-acting venoms of any land snake.

Combined with its reputation for aggression (at least when cornered) and you’ve got a big, intimidating, deadly, ornery serpent that can probably outrun you. It’s not the most obvious place to go looking for painkillers.

But among the cocktail of chemicals in the black mamba’s venom, Sylvie Diochot and Anne Baron from the CNRS have found a new class of molecules that can relieve pain as effectively as morphine, and without any toxic side effects. They’ve named them mambalgins.

Diochot and Baron started by searching animal venoms for chemicals that could block ASICs – not the shoe manufacturer, but a group of pain-inducing proteins called acid-sensing ion channels. They’re like miniature gates, which dot the surface of neurons.

When we’re injured, our damaged cells release an “inflammatory soup” of chemicals that triggers feelings of pain. Among the first of these harbingers are simple protons – positively charged particles that make the local tissues more acidic. The ASICs detect and respond to protons by opening up, allowing positive ions to flood inside, and causing the neurons to fire. They’re warning systems that tell our bodies that something is wrong.

Diochot and Baron found two peptides (short proteins) from black mamba venom that block ASICs—mambalgin-1 and mambalgin-2. They act as padlocks that latch onto the closed proteins and stop them from opening, even when surrounded by protons. And they have characteristics that are almost too good to be true.

They work quickly and effectively against every type of ASIC found in our nervous system. As painkillers, they’re as potent as morphine. They’ll numb the sharp pain of a burn, as well as the dull throb of an inflamed limb. They’re incredibly specific: they don’t stop neurons from firing more generally, and they don’t block any of the other gate-keeping proteins found in these cells. And unlike other similarly shaped proteins, they don’t have any toxic effects, such as paralysis, convulsions or breathing difficulties. (The list of side effects that Diochot and Baron checked for, and saw no sign of, includes “death”; good to know.)

Animal venoms, of course, are better known for causing pain rather than dulling it. Many work through ASICs too. The Texas coral snake, for example, has venom that causes excruciating pain, thanks to a toxin called MitTx that makes ASICs much more sensitive to protons. The Trinidad chevron tarantula uses a different toxin that locks ASICs in their open state, allowing them to constantly trigger sensations of pain.

So why does the black mamba have potent painkillers in its arsenal? No one knows, but it’s not alone. “Cobra venom, and more recently the corresponding purified cobrotoxin, have been used for instance for the control of pain in traditional Chinese medicine,” says Baron. But cobrotoxin can also paralyse muscles; mambalgins, on the other hand, kill pain and little else.

The team is now exploring the properties of mambalgins even further. They’re years away from turning these proteins into usable painkillers, but they’ve already been granted a patent, and found an industrial partner –a company called Theralpha that specializes in treatments for pain.

In the meantime, the mambalgins are already teaching us more about the basis of pain. In the central nervous system – the brain and spine –they mainly work by blocking a specific ASIC known as ASIC1a. If mice don’t have this protein, mambalgins do nothing for them.

But it’s a different story in the peripheral nervous system – the nerves that branch through the rest of our body. There, mambalgins are more than capable of relieving pain, even in mice that lack ASIC1a. That’s because they work by blocking a different ASIC known as ASIC1b, whose role in pain has been unclear until now.

So, the black mamba has provided us with two leads in the quest for a better painkiller. Its venom has helped to identify proteins that could be targeted to soothe pain in the central and peripheral nervous systems, and it has given us two chemicals that could potentially do the job.

Reference: Diochot, Baron, Salinas, Douguet, Scarzello, Dabert-Gay, Debayle, Friend, Alloui, Lazdunski & Lingueglia. 2012. Black mamba venom peptides target acid-sensing ion channels to abolish pain. Nature.

Image by Bill Love/Blue Chameleon Ventures

CATEGORIZED UNDER: Molecular biology, Reptiles, Snakes

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