Scorpion toxin uncovers insights into pain that could inspire non-opioid treatments

A protein called TRPA1 is informally known as the “wasabi receptor,” because it resides in nerve cells and is responsible for creating the sinus-clearing response people generally have when they consume the Japanese horseradish that comes with every order of sushi. Now, a team of researchers from the University of Queensland and the University of California, San Francisco (UCSF) has discovered a toxin that targets the wasabi receptor via a previously unknown mechanism—one that could inspire new treatments for chronic pain.

They isolated the toxin from the venom of the Australian black rock scorpion and dubbed it WaTx (wasabi receptor toxin). The researchers probed the toxin and discovered that it triggers TRPA1 by forcing its way into nerve cells. That makes it different from most compounds, which have to endure much more complex processes to gain entry to cells. They published the findings in the journal Cell.

The team discovered that WaTx has a specific sequence of amino acids that allows it to speed its way into the interior of the cell—something most proteins can’t do.

That’s important, because “if you understand how these peptides get across the membrane, you might be able to use them to carry things—drugs, for example—into the cell that can't normally get across membranes,” said lead author John Lin King, a doctoral student in UCSF's neuroscience program, in a statement.

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The researchers found another key characteristic of WaTx they believe could further enhance the development of new treatments for chronic pain. Once inside the nerve cell, the toxin attaches itself to the same site on TRPA1 wasabi and other irritants target. But rather than triggering both pain and inflammation, it only causes pain. That’s because it “props up” a TRPA1 channel that allows positively charged sodium ions to flood in and cause pain, but not enough calcium ions to trigger inflammation.

They confirmed their discovery by observing the reactions of mice exposed to either WaTx or mustard oil, which also activates the wasabi receptor. WaTx caused pain sensitivity but not swelling.

“Our results suggest that you can decouple the protective acute pain response from the inflammation that establishes chronic pain,” Lin King said. “Achieving this goal, if only in principle, has been a longstanding aim in the field.”

With opioid-addiction rates at crisis levels, the search for non-opioid pain killers has become a priority among researchers. And TRPA1 is already a target for some working in the pain field. Earlier this year, India’s Glenmark established a U.S.-based spinoff to develop several new molecular entities, including a TRPA1 agonist that’s currently in phase 2 trials to treat pain from diabetic neuropathy. Last year, Eli Lilly acquired TRPA1 agonists from Hydra Biosciences in the hopes of developing them to treat chronic pain.

Scorpion venom has inspired more than just pain research. Blaze Bioscience is now running a pivotal trial of a fluorescent molecule derived from the deathstalker scorpion that illuminates cancer cells, making it easier for surgeons to spot and remove tumors. And last year, scientists in Spain reported they developed a compound from the venom of giant yellow Israeli scorpions that they believe could be used to shuttle drugs across the blood-brain barrier.

The UCSF and Queensland researchers believe their findings validate TRPA1 as a target for new pain drugs. They hope their observations will also help elucidate the link between chronic pain and inflammation—and differences between them that could be exploited in the development of non-opioid pain relievers.