An African tarantula's harsh bite could unlock new pain treatments

The king baboon spider’s venom packs a powerful punch. While not lethal in humans, its bite leaves a sharp, burning ache. But the pain may have a silver lining. In a new study, researchers reveal how the king baboon spider’s venom causes such extreme pain. The findings could help scientists pinpoint why humans experience chronic pain — and how to treat it.

What’s new — The king baboon spider (Pelinobius muticus) is a type of African tarantula that spends most of its time underground minding its own business, but these researchers sought to understand why its bite induces such severe pain in humans.

They found that the animal’s venom seems to induce hyperexcitability in nerve cells called nociceptors, which, in turn, causes the extreme pain people can experience when they are bitten by the spider.

Curiously, scientists have observed similar activity in the neurons (a kind of brain cell) of people with chronic pain who have nerve damage. By understanding how hyperexcitability works, doctors may be able to better treat this type of chronic pain.

“This study has provided an understanding of the cellular [and] physiological mechanisms behind painful P. muticus [venom],” study co-authors Rocio K. Finol-Urdaneta, David J. Adams, and Paul F. Alewood, tell Inverse. The researchers work at the llawarra Health and Medical Research Institute and the Institute for Molecular Bioscience at the University of Queensland.

The study was published Monday in the journal Proceedings of the National Academy of Sciences.

How they did it — Scientists don’t understand the biological mechanisms behind why spider bites can cause extreme pain in their human victims — in part because spider venom is extremely complex.

“There are many components in spider — and other animals’ — venoms able to cause pain, yet the particular ‘cocktail’ delivered by each spider will determine the mechanisms through which pain is elicited,” the researchers say.

Finol-Urdaneta and his colleagues focused on a key component in king baboon spider venom: a peptide known as Pm1a, which modulates receptors in the dorsal root ganglion. This is a cluster of sensory neurons in the brain that convey information going to and coming from the central nervous system, thereby causing “hyperexcitability in pain neurons.” Hyperexcitability in this context essentially means the pain neurons repeatedly, spontaneously fire, causing the sensation of extreme pain.

To better understand how spider venom induces hyperexcitability in pain neurons, the researchers created a synthetic version of the Pm1a peptide. Then they injected this peptide into the paws of mice to see if it would produce a similar pain response as the one induced by the real peptide found in the spider venom.

The scientists also isolated the nociceptors — pain-tuned nerve cells — and analyzed how the peptide acts on voltage-gated sodium, potassium, and calcium channels. These types of channels are associated with a cellular phenomenon known as “action potential generation,” which is necessary for neurons to receive electrical signals from external stimuli. In this case, the external stimulus is the pain from the spider venom.

Then, to confirm all these findings, the researchers created a computer model of a pain neuron to test their hypothesis.

The scientists discovered the mice’s pain neurons fire “significantly more” in the presence of the synthetic version of the Pm1a peptide.

The increase in firing (again, known as hyperexcitability) produces heightened sensitivity to pain. The spider venom creates this sensitivity to pain by modulating sodium ion and potassium channels, leading to increased “spontaneous firing” of the action potentials on pain neurons.

As the researchers write in the paper:

Spontaneous activity and increased firing frequency of nociceptors are the key sources of pain in the peripheral nervous system.

Why it matters — Part of why this study is so interesting is that similar spontaneous neuron firing has also been observed in people with chronic who experience nerve damage. The similarities in hyperalgesia — extreme sensitivity to pain — in king baboon spider victims and people with chronic pain could yield new insights for medications targeting chronic pain at its source.

Understanding the “physiological process of pain” generated by spider venom could help us develop therapeutic treatments for humans poisoned by spider venom. And by learning how a single peptide in spider venom can modulate “a multitude” of sodium ion channels to generate pain, we can better understand the evolution and toxic efficiency of spider venom.

But beyond that, there are similarities in the biological mechanisms that cause pain in king baboon spider venom victims as well as people with chronic pain. Understanding the similarities between the two pain pathways could lead to the development of drugs for chronic pain.

The researchers speculate that “drugs that could reduce excitability in pain neurons through the simultaneous modulation of several molecular players may provide more effective, alternative treatments for pain.”

What’s next — The researchers are careful to point out that while this study is interesting, there are many more questions that remain about the potential interactions of the Pm1a peptide with other biological mechanisms, and how these might factor into the chronic pain experienced by humans with no clear cause (unlike the pain caused by a spider sinking its fangs into your leg).

Only more research can answer these questions, and, ultimately, help pave the way for future pharmaceutical treatments for chronic pain.

“Detailed studies directed to determine the specific molecular interactions of Pm1a with its many targets may inform the development of pharmacological analogs that could decrease excitability specifically in pain neurons,” the researchers conclude.

Abstract: The King Baboon spider, Pelinobius muticus, is a burrowing African tarantula. Its impressive size and appealing coloration are tempered by reports describing severe localized pain, swelling, itchiness, and muscle cramping after accidental envenomation. Hyperalgesia is the most prominent symptom after bites from P. muticus, but the molecular basis by which the venom induces pain is unknown. Proteotranscriptomic analysis of P. muticus venom uncovered a cysteine-rich peptide, δ/κ-theraphotoxin-Pm1a (δ/κ-TRTX-Pm1a), that elicited nocifensive behavior when injected into mice. In small dorsal root ganglion neurons, synthetic δ/κ-TRTX-Pm1a (sPm1a) induced hyperexcitability by enhancing tetrodotoxin-resistant sodium currents, impairing repolarization and lowering the threshold of action potential firing, consistent with the severe pain associated with envenomation. The molecular mechanism of nociceptor sensitization by sPm1a involves multimodal actions over several ion channel targets, including NaV1.8, KV2.1, and tetrodotoxin-sensitive NaV channels. The promiscuous targeting of peptides like δ/κ-TRTX-Pm1a may be an evolutionary adaptation in pain-inducing defensive venoms.