A Safe Alternative To Opioid Painkillers Could Come From Tarantula Venom

Many people have no love for spiders. But some of the venomous arthropods could hold the key to unlocking a painkiller that rivals opioids in effectiveness, but without the damaging side-effects, such as addiction.

Scientists have modified the neurotoxic venom of a tarantula called the Chinese bird spider (Cyriopagopus schmidti) to produce a protein that acts as a powerful painkiller. So far, it's proven effective in mice.

"Our findings could potentially lead to an alternative method of treating pain without the side-effects and reduce many individuals' reliance on opioids for pain relief," said chemical biologist Christina Schroeder of the University of Queensland in Australia.

Opioids - drugs derived from the latex of opium poppies, as well as synthetic and semi-synthetic versions - are among the best tools we have for treating various types of pain. But they're also hugely addictive, and overdose can be deadly. In 2018, opioids were involved in 46,802 overdose deaths; the White House has called it "the worst drug crisis in US history".

Even when these drugs are used as prescribed, it's not always smooth sailing. Common side effects include dizziness, nausea, drowsiness, constipation, and difficulty breathing.

The myriad problems with opioids have driven researchers to hunt for alternatives, leading to the exploration of the neurotoxic venom of snakes, arachnids, and even sea snails. These venoms affect the nervous system, and their numbing and paralytic properties can be exploited to relieve pain once the deadly part has been extracted or neutralised.

The venom of Chinese bird spiders contains a peptide that has also been explored in this context. It's called Huwentoxin-IV, and it works by inhibiting activation of the voltage-gated sodium channels required for the flow of sodium ions that can trigger pain receptors in the nervous system.

Previous work showed that this peptide can be exploited to dull pain in rats. But - aside from the effect on the sodium channels - Schroeder and colleagues later showed the importance of the cell membrane in this interaction, too.

Now, they have manipulated Huwentoxin-IV to improve its affinity for the cell membrane, to promising effect.

"Our study found that a mini-protein in tarantula venom from the Chinese bird spider, known as Huwentoxin-IV, binds to pain receptors in the body," Schroeder explained.

"By using a three-pronged approach in our drug design that incorporates the mini-protein, its receptor and the surrounding membrane from the spider venom, we've altered this mini-protein resulting in greater potency and specificity for specific pain receptors."

This ensures, she said, that the correct amount of Huwentoxin-IV attaches to the cell and cell membrane. And, when tested in mice, the most potent of the analogues the team developed resulted in a significant decrease in pain response compared to the control.

It's far from close to being ready, but each step in investigating how venoms work to dull pain brings us a little closer. And the team hopes that soon, we will be able to get closer still.

"We anticipate that new technologies, including cryogenic electron microscopy, will help us to overcome current limitations and allow future studies to focus on investigating the three components simultaneously, providing a complete picture of the different interactions," they wrote in their paper.

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