What causes pain that feels like walking over flaming charcoal with a 3-inch nail embedded in your heel? The culprit is no bigger than the size of your thumb. Paraponera clavata, also known as the bullet ant, is an ant native to the South American rainforest [1]. The ant gets its common name from the long lasting and intense pain caused by its sting, which many people find comparable to being shot with a bullet. Despite the pain, its sting is not lethal and does not cause any serious damage. In fact, tribes native to the ant’s region of origin would perform a ritual in which young boys must prove their manhood by wearing a glove composed entirely of bullet ants woven between leaves [2]. The advantage of a pain inducing sting that doesn’t easily kill is that the victim will live to remember the pain and avoid messing with the ants in the future. If the sting were lethal, the victim would not be able to learn or pass on the knowledge that these ants should be avoided to its offspring. This can lead to more ant deaths since there will be more attempts by unaware predators to target these ants for food. Since the sting is painful but not dangerous, scientists see it as a unique system to study how pain works. This research may lead to a better understanding and new treatments for certain chronic pain disorders. So how is the sting so painful yet not dangerous?
To understand the reason why the bullet ants sting is so agonizing, we must first consider how our bodies detect painful stimuli and how that sensation is carried to the brain. Our skin is innervated by sensory neurons, called nociceptors, with the purpose is to detect damage causing sensations and transmit this information to the brain. Different forms of pain activate the nociceptors differently, but the mechanism always involves an influx of positively charged ions into the cell. As the positive charge builds up in the cell, it activates nearby voltage gated sodium channels. These channels have several components that allow it to exist in three states. When the charge in the cell is low, a component called the activation gate keeps the channel closed, preventing passage of sodium ions. When the charge is high enough, a voltage sensing component will cause the activation gate to open. This allows sodium to enter, and since sodium is positively charged, the charge inside the cell increases further allowing neighboring voltage gated sodium channels to open. To prevent overactivation, the channels do not stay open for very long, so shortly thereafter, a component called the inactivation gate moves in to block the channel until the local charge around the channel returns to normal. The rapid opening and closing of the voltage gated sodium channels creates a chain reaction of voltage gated channel openings that propagates along the neuron all the way to its nerve terminal in the spinal cord. When the charge reaches the terminal, it triggers the release of neurotransmitters which activate neurons in the spine that relay the signal to the brain, where the perception of pain occurs.
Normal pain sensation begins when painful stimuli activate nociceptive neurons. The signal is relayed to the spine and then to the brain where pain perception and localization happens.
So how does the bullet ants sting affect pain? Basically, bullet ant venom causes the pain sensing neurons to fire by bypassing the stopping mechanism in a way that leads to intense and ceaseless pain. Within the bullet ants’ venom is a small peptide called Poneratoxin. Poneratoxin induces pain by interacting with the voltage gated sodium channels. All neurons have voltage gated sodium channels but different cells have different types. One type, called Nav1.7, is mainly found on pain sensing nociceptors. Poneratoxin selectively binds to Nav1.7, and makes it impossible for the inactivation gate to close. As a result, the mechanical damage caused by the sting itself causes Nav1.7 to open and the charge rises in the cell, but since the channel can't close, sodium continually flows into the cell causing the charge to remain high. This results in ceaseless activation of the nociceptor which relays the signal to the spinal cord and as a result the brain receives a continuous pain signal [3].
Ponera toxin binds to voltage gated sodium channels on nociceptive neurons. Poneratoxin binding prevents sodium channel inactivation. Continuous entry of positively charged sodium ions leads to continuous activation of nociceptors.
An illustration of this mechanism can be seen in this video:
(url: https://www.youtube.com/watch?v=cXivTK5-rZY)
When scientists learned of the pain inducing mechanism of the bullet ant, they wanted to use this knowledge to better treat people afflicted with chronic pain disorders. It was later discovered that certain pain disorders are caused by mutations in the gene for Nav1.7 [4]. These mutations can lead to either an overactive or underactive version of the protein. People with inherited erythromelalgia have overactive Nav1.7 and as a result become hypersensitive to pain [5]. Meanwhile people with underactive Nav1.7 become insensitive to pain [6]. This discovery spurred the development of drugs that can specifically block Nav1.7. Drugs that block Nav1.7 have been successful in treating pain for people with inherited erythromelalgia [7,8]. This result highlights how curiosity about a venom's mechanism can lead to discovery of new targets to treat diseases. This is only the beginning, however, as many pain disorders have different causes and thus different drugs are needed for different disorders. Further study of how natural molecules, such as those found in venoms, could potentially lead to new ways of treating pain.
References
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Bosmia, Anand N., et al. “Ritualistic Envenomation by Bullet Ants Among the Sateré-Mawé Indians in the Brazilian Amazon.” Wilderness & Environmental Medicine, vol. 26, no. 2, Elsevier, June 2015, pp. 271–73, doi:10.1016/J.WEM.2014.09.003.
Piek, Tom, et al. “Poneratoxin, a Novel Peptide Neurotoxin from the Venom of the Ant, Paraponera Clavata.” Comparative Biochemistry and Physiology Part C: Comparative Pharmacology, vol. 99, no. 3, 1991, pp. 487–495., doi:10.1016/0742-8413(91)90276-y.
Dib-Hajj, Sulayman D., et al. “From Genes to Pain: Nav1.7 and Human Pain Disorders.” Trends in Neurosciences, vol. 30, no. 11, Elsevier Current Trends, Nov. 2007, pp. 555–63, doi:10.1016/J.TINS.2007.08.004.
Y, Yang, et al. “Mutations in SCN9A, Encoding a Sodium Channel Alpha Subunit, in Patients with Primary Erythermalgia.” Journal of Medical Genetics, vol. 41, no. 3, J Med Genet, 2004, pp. 171–74, doi:10.1136/JMG.2003.012153.
Cox, James J., et al. “An SCN9A Channelopathy Causes Congenital Inability to Experience Pain.” Nature 2006 444:7121, vol. 444, no. 7121, Nature Publishing Group, Dec. 2006, pp. 894–98, doi:10.1038/nature05413.
L, Cao, et al. “Pharmacological Reversal of a Pain Phenotype in IPSC-Derived Sensory Neurons and Patients with Inherited Erythromelalgia.” Science Translational Medicine, vol. 8, no. 335, Sci Transl Med, Apr. 2016, doi:10.1126/SCITRANSLMED.AAD7653.
Hameed, Shaila. “Nav1.7 And Nav1.8: Role in the Pathophysiology of Pain.” Molecular Pain, vol. 15, 2019, p. 174480691985880., doi:10.1177/1744806919858801.
