Potent, Lethal Pufferfish Poison Has Unexpected Role in Relieving Pain

When a pufferfish is filleted, one wrong slip of the knife can turn the seaborne delicacy deadly. Even in death, the pufferfish’s natural poison, called tetrodotoxin, is more poisonous than cyanide for anyone that ingests it. But scientists are interested in the potent toxin for another reason: its uncanny ability to fight pain.

Tetrodotoxin is found in the puffer’s, liver, intestines, gonads, and skin, but not the meat. If you cut the fish right, it’s safe to eat, but inevitably a badly sliced piece of pufferfish sushi, called fugu, kills at least one adventurous eater now and then. But in a paper published Wednesday in Nature Communications, Daniel Kohane, M.D., Ph.D., at Boston Children’s Hospital debuts a method for binding and controlling the toxin that could open it up to a variety of clinical uses, including managing pain.

“I mean, to show you how safe this stuff is, in the paper, we injected an animal with polymer that had 20 micrograms of tetrodotoxin in it,” Kohane, a senior associate in critical care medicine, tells Inverse. “That’s enough to kill rats like 10 times over, and they didn’t experience any signs of toxicity. So this stuff is really really safe.”

Kohane and his co-authors Chao Zhao, Ph.D., and Andong Liu, Ph.D., who are also at Boston Children’s Hospital, are interested in tetrodotoxin because they hopes it might serve as a local pain reliever similar to lidocaine or bupivacaine. Anesthetics like these are “used like water in clinical medicine,” says Kohane. But he thinks that the pufferfish’s greatest weapon is uniquely suited for the job.

“It is very potent, which means that a very small amount of stuff has a very big effect,” he explains.

Tetrodotoxin is a sodium channel blocker, which means that it clogs off channels on the cell membrane. By blocking those channels, the toxin keeps nerve cells from firing correctly. Ironically, that’s also how the toxin kills — once it spreads, it paralyzes the diaphragm, resulting in death by asphyxiation. But,Kohane believes that if we can deliver tetrodotoxin directly into damaged tissues and control its release, we may be able to use its ability to block sodium channels to our advantage.

“Unlike other drugs of its class, site one sodium channel blockers seem to not cause seizures or heart arrhythmia, and don’t have much local tissue toxicity, which is a problem with conventional local anesthetics,” he says.

Other local painkillers work by blocking sodium channels too, he adds. “Most local anesthetics work by blocking sodium channels. That we didn’t invent, God made that,” he jokes. But what he did do is find a way to control the otherwise toxic substance by controlling its release. In the new paper, Kohane and his team did this by binding the neurotoxin to a polymer backbone, creating strong chemical bonds that, once in the body, release the toxin slowly into a targeted tissue, like the sciatic nerve, which he tested in his rat models.

In some cases, the toxin is bound so tightly that it can be slowly released into tissues for as long as three days in his rat models, suggesting that it could help numb pain for that long, or perhaps, he hopes even longer. He’s going for longer periods of time that might be of use to people with persistent injuries for weeks or even months.

"It is very potent, which means that a very small amount of stuff has a very big effect."

“What we showed is that we can attain a whole range of durations of block,” Kohane says. “And so, different lengths are appropriate for different things. You can imagine for someone with cancer pain for example, they might want a really long nerve block, in fact, the longer the better.”

Whenever we talk about chronic pain, it’s tempting to apply the findings to the current opioid overdose crisis. Opioids were responsible for an estimated 47,600 deaths in 2017, so for good reason, scores of researchers have been searching for coveted alternatives to traditional opioids, which, because they involve the brain’s reward pathways, can lead to addiction.

Kohane is hopeful for his therapy, which takes aim at local chronic pain specifically. But like other proposed alternatives, from snail venom to rewiring pain in the brain, his method still needs to be translated to humans. That, he notes, is “unpredictable.” But a silver lining here is that he believes the technology is scalable. It probably would be fairly straightforward to make and use, he adds.

But whether or not his study is the answer to the bigger issues around chronic pain, they indicate a new hope. Somewhere out there in nature, there’s a better way to deal with chronic conditions like pain, even if it’s deadly to us now. We just need to find the right ways to use it.

Abstract: There is clinical and scientific interest in developing local anesthetics with prolonged durations of effect from single injections. The need for such is highlighted by the current opioid epidemic. Site 1 sodium channel blockers such as tetrodotoxin (TTX) are extremely potent, and can provide very long nerve blocks but the duration is limited by the associated systemic toxicity. Here we report a system where slow release of TTX conjugated to a biocompatible and biodegradable polymer, poly(triol dicarboxylic acid)-co-poly(ethylene glycol) (TDP) is achieved by hydrolysis of ester linkages. Nerve block by the released TTX is enhanced by administration in a carrier with chemical permeation enhancer properties. TTX release can be adjusted by tuning the hydrophilicity of the TDP polymer backbone. In vivo, 1.0–80.0 μg of TTX released from these polymers produced a range of durations of nerve block, from several hours to 3 days, with minimal systemic or local toxicity.