How South American tribes harnessed ion channel poisons

As children, many of us loved reading stories about the adventures of indigenous South American Indians, vividly depicted in novels like James Fenimore Cooper’s The Last of the Mohicans. These stories sparked our imaginations and took us on thrilling journeys through unexplored landscapes.

Living in constant warfare with other tribes or colonizers, the South American Indians were skilled warriors and hunters, adept at throwing tomahawks and archery with precision. Some even prepared their arrows with something far more dangerous than sharp tips – poison.

One of the most famous poisons used was curare. Extracted from plants like Strychnos toxifera and Chondrodendron tomentosum, this potent substance could bring down large animals and adversaries alike with terrifying efficiency.

Curare’s active ingredients, primarily d-tubocurarine, bind to and block nicotinic acetylcholine receptors (nAChR) at neuromuscular junctions, preventing acetylcholine from attaching and activating them. Essentially, curare causes muscles to relax so profoundly that the victim can no longer move. And if it reaches the respiratory muscles, it can be fatal because the victim cannot breathe.

If only the victims knew that in the same forests where tribes used curare, amidst the creeping vines and towering trees, grew the Manchineel tree. Notoriously dangerous in its own right, this tree also bears fruits containing physostigmine, a natural antidote to curare’s lethal effect.

Physostigmine inhibits the enzyme acetylcholinesterase (AChE), which breaks down acetylcholine. By inhibiting AChE, physostigmine allows acetylcholine levels to build up at neuromuscular junctions, increasing the chances that acetylcholine can outcompete curare for nAChR receptor sites.

Isn’t it fascinating how in the same place where you find a dangerous poison, you also find its cure?

Interestingly, the properties of curare have found a place in modern medicine. Muscle relaxants like curare are now used in anesthesia to provide optimal operating conditions. By allowing surgeons to perform delicate procedures with minimal movement from the patient, these muscle relaxants have revolutionized surgery. However, this use is not without its risks.

While these muscle relaxants help reduce the necessary dose of anesthetics, they can also pose significant problems. If the dose of anesthetic is insufficient, the patient could regain consciousness during surgery, unable to move or communicate due to paralysis from the muscle relaxant. In such rare but horrifying cases, some patients report experiencing the full intensity of surgical pain while being powerless to alert the surgical team.

Awareness under anesthesia affects about 0.2% of patients. Given the WHO’s estimate of 230 million major surgeries annually, and assuming that a significant portion (e.g., 80%) require general anesthesia, around 350,000 people could experience this state each year, with about 100,000 of them feeling every movement of the surgeon’s scalpel.