One of the world’s most poisonous snakes might hold the key to new pain therapies in its venom.
As ironic as that sounds, a protein component in black mamba venom called “mambalgin” has been shown – in a Nature paper published today – to act as a pain killer in mice.
The snake is found primarily in central and southern Africa, where it is widely – and justifiably – feared. As with the venom of other poisonous snakes, the black mamba’s venom is a complex mixture of toxins.
A bite from this snake can deliver more than 100mg of venom but as little as 10-15mg can be fatal for humans. Initial symptoms can include dizziness, breathing difficulties and convulsions, and death can occur within half an hour if an antidote is not administered.
On the plus side, toxins are highly evolved proteins with structural features that allow them to interact with other proteins, and influence their function. This makes toxins good scaffolds for making potent modulators of other proteins' functions.
Several research groups have examined the venoms of different poisonous animals and plants, looking for useful tools with which to explore biological functions, such as pain sensation and muscle control.
In some cases, they have used these tools to generate useful drugs, such as Prialt from cone snail venom – used to treat pain that doesn’t respond to other pain-relieving drugs – and Captopril from snake venom – a ground-breaking high-blood-pressure medicine.
Pain-sensing nerves are specialised cells which respond to noxious stimuli, such as acid or heat. Upon contact with these stimuli, they open sensor-activated protein ion pores (“ion channels”) on their surface.
Ion channels let small electrical currents pass down an electrical gradient to trigger nerve signals. These signals pass to nerves in the spinal cord, then on to the brain, where we interpret them as pain.
Sensor-activated ion channels are key to triggering nerve firing. Finding toxins that can open or close ion channels helps us to understand how and why ion channels work. Some toxins are very painful, because they activate pain-related ion channels, such as the chili pepper receptor TRPV1 in the case of tarantula venom or the acid-sensing ion channel in the case of the Texas coral snake.
But some toxins stop pain-related ion channels opening, so may help us determine the role of individual ion channels or even be new therapies to treat pain.
What the new paper shows
The nature paper published today by Sylvie Diochot, from the Institut de Pharmacologie Mole´culaire et Cellulaire in France, and colleagues describes two black mamba venom toxin components (mambalgins) that block acid-sensing ion channels (ASICs) in peripheral, pain-sensing nerves and central pain pathways.
These toxins exert profound analgesic effects in mouse models of pain by blocking ASIC in these two pathways via both an opioid-dependent and opioid-independent pathway. Even the opioid-independent mechanism has the same strong effect as that of opioids such as morphine.
The new opioid-independent pain-killing mechanism is very interesting, because it may reduce the risk from overdoses that cause respiratory depression – the most dangerous form of opioid overdose. It may also reduce the risk of addiction associated with opioid drugs.
Pain responses in animals can be due to drowsiness or muscle relaxation caused by the agent being tested. According to the authors, the experiments described in the paper show no signs of these confounding effects that could give a false impression of pain-killing action.
From this paper, it looks like the black mamba toxin may contain a new component, mambalgin, that can be used to develop new pain therapies.
What happens now?
It’s possible, but unlikely, that one of the mambalgin proteins identified will be used as medicine without any more changes being made to it.
But pharmaceutical companies and publicly funded research groups will probably look for small molecules that can mimic the actions of mambalgins to produce potent, orally available drugs to treat pain. Unfortunately, this process could take up to ten years to complete.
Pain is poorly treated currently and there is a dire need for new and more effective drugs to improve the quality of life of people with pain.
So, we should wish these research groups the best of luck!