Try not to annoy the king baboon spider, a tarantula native to Tanzania and Kenya: Its excruciating bite can cause days of pain, swelling, and muscle spasms in humans.
With that in mind, it may seem ironic that a new study suggests the spider could one day inspire new kinds of painkillers. According to the researchers, who published their findings in Proceedings of the National Academy of Sciences, the inner workings of the tarantula’s venom could help explain mysteries of chronic pain that have plagued patients and stumped scientists for years.
Spider bites are practically synonymous with pain. “One of the hallmarks of spider bites is the sensation of pain,” said Rocio Finol-Urdaneta, a co-author of the study who conducts research at the Illawarra Health and Medical Research Institute in Australia. When patients go to doctors with bites, “The first question is does it hurt or not, because that’s the criteria.” So studying spider bites can help scientists understand how pain works.
Tarantula venom seems fine-tuned by nature to defend against predators and incapacitate prey. But researchers often find new and surprising uses for natural toxins. Snake venom has long been used to make anti-venom, and last year Vox reported on a weight-loss drug inspired by lizard venom.
And because many aspects of pain remain puzzling to scientists, they stand to learn a lot from a spider venom that may have evolved to inflict as much of it as possible. “Pain is our body’s great harm alarm, developed a kajillion years ago,” explained Sean Mackey, chief of pain medicine at Stanford University, who is unaffiliated with the tarantula study. “It’s rather deeply wired into us, because without pain we wouldn’t live very long.”
The big picture of pain is simple enough: Our bodies are covered with nerve cells, known as sensory receptor neurons, that are either excited or inhibited by stimuli like temperature, pressure, or chemicals. Some of these neurons are pain-response neurons that send warnings through our nerves to the brain when something is wrong. The brain then turns that signal into the sensation of pain.
“We all live in a balance of excitation and inhibition,” said Mackey. When our sensory neurons are functioning normally, they fire and relax in the span of milliseconds to create all kinds of sensations — say, the warmth of a cozy fire on your skin. But sometimes this balance breaks down and the pain neurons fire, but they don’t relax. The body’s alarm system malfunctions, causing chronic pain. The venom of the king baboon spider is particularly good at hijacking the electric processes that tell our neurons whether to fire or relax.
So how do pain neurons know when to get excited or relax? Each one is encircled by millions of little doors that are custom-made for charged particles, such as sodium, potassium, and calcium ions, that flow in and out of the neuron. Sodium ions, for example, excite neurons, and neurons release potassium ions to calm back down.
Here’s the problem with king baboon spider venom: It contains a peptide called Pm1a that opens the doors (also called channels) for sodium ions while also closing potassium ion channels. Sodium ions keep marching in through the open sodium doors, and the exit doors for the potassium ions are being held shut from the outside, so the neuron can’t calm back down. “It’s a double whammy,” said Mackey. “What you end up with is severe pain.”
Many modern painkillers, or analgesics, work by simply blocking a few ion channels, refusing to let anything pass and maintaining the neuron’s chill, unexcited state. But neurons can become desensitized to those drugs, which often leads doctors to prescribe higher doses. That’s one reason that opioids — the most powerful form of painkillers we have today — can cause addiction and lose their efficacy over time.
“The benefit of using spider-derived venom peptides are that these peptides do not cause dose dependence and addiction,” said Christina Schroeder, a researcher at NIH who studies venom-inspired painkillers but did not work on the tarantula study, in an email to Vox. They don’t rely on the receptors that oxycodone or morphine would latch onto, and they can also be more precise than opioids, Schroeder added, reducing their side effects.
While some peptides found inside spider venom are very good at causing pain, other venoms contain peptides that actually prevent pain. In the past, studies have looked for peptides in venom that are “selective” for a specific channel (Nav1.7) often associated with chronic pain. “We’re kind of selectivity-obsessed in the field,” said Finol-Urdaneta.
The findings around the king baboon spider seem to suggest that an alternative approach is possible. The tarantula’s venom isn’t selective; it hits as many ion channels as it can. Finol-Urdaneta and her co-authors, who work at the University of Queensland and the Victor Chang Cardiac Research Institute, call the peptide “promiscuous” because of how easily it can affect different channels. This means an individual neuron is unlikely to become desensitized — and continuous exposure to the peptide causes continuous pain (ouch).
“Imagine if you engineer a different peptide that does just the opposite, blocking sodium channels and opening potassium channels,” said Mackey. “Now you’ve got an analgesic that is promiscuous and operating in a much different way than any of our current drugs.”
That would make for an extremely effective painkiller, experts told Vox. “This study highlights that we should probably reexamine the way we approach the development of novel pain therapeutics,” wrote Schroeder. Instead of designing drugs to selectively focus on a handful of ion channels, Schroeder said, researchers should focus on painkillers that target several parts of our pain-sensing systems.
These kinds of potential treatments are still quite a way off, said Mackey. Now that Finol-Urdaneta and her team have determined what the peptide does, the next step is to study how it works on a molecular level — and, down the line, whether the process can be reverse-engineered to relieve rather than cause pain.
“It’s easier said than done,” Finol-Urdaneta said. “Nature has been practicing with this for millions of years.”