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= Schmidt sting pain index =

Overview
Schmidt's pain scale of Hymenopteran stings is organized into levels, ranging between below 1 to 4, with 4 being the most painful. However, insect stings that feel very differently can be put into the same level. Thus, Schmidt always includes a brief description of his experience being stung by each type of insect. On that note, these stings are based on Schmidt's subjective perspective, and insect stings can vary person to person, so the scale is not universal.

Pain Level 1
Some of the insect stings Schmidt considers to be at a pain level of 1 include the Southern fire ant, the Elongate twig ant, the Western paper wasp, the white-faced bee, and most small bees. The duration of the pain of insect stings categorized into Pain Level 1 generally is five minutes or less.

Since many small bees are categorized into a pain level of 1, it should be noted that the most toxic polypeptides in bee venom are melittin, apamin, and MCD peptide. Melittin is the main toxin of bee venom, and it damages red blood cells and white blood cells. Apamin is a neurotoxin that augments polysynaptic reflexes. MCD peptide destroys mast cells.

Feeling only slight pain, Schmidt has described the sting of the Anthophorid bee, categorized into Pain Level 1, as “almost pleasant, a lover just bit your earlobe a little too hard.” Also rated into Pain Level 1, Schmidt has described the sting of the sweat bee as "light, ephemeral, almost fruity. A tiny spark has singed a single hair on your arm."

Pain Level 2
Schmidt sets the sting of the Western honey bee at a pain level of 2 to be the anchoring value, basing his categorization of all other stings off of it. He has categorized a variety of wasps, bees, and ants into Pain Level 2, including the yellowjacket, the Asiatic honey bee, and the trap-jaw ant. The duration of the stings in this level is generally between five to ten minutes long. Schmidt categorized the majority of Hymenopteran stings as having a pain level of 2.

The sting of a termite-raiding ant, categorized as a pain level of 2, has a similar feeling as "the debilitating pain of a migraine contained in the tip of your finger," according to Schmidt. On the contrary, the yellowjacket's sting was described as being "hot and smoky, almost irreverent. Imagine W. C. Fields extinguishing a cigar on your tongue." Though the sting was a different feeling, the yellowjacket was also rated at a pain level of 2.

Pain Level 3
Most insects that are characterized as having a pain level of 3 are wasps, including the red paper wasp, the metricus paper wasp, and the velvet ant (which is actually a wasp, not an ant). The duration of the sting pain can range anywhere from one minute (such as the sting of the red paper wasp) to half an hour (such as the sting of the velvet ant). Wasp venom uniquely contains wasp kinin that exhibit kininlike activity. One of the kinins found in wasp kinin, polistes kinin 3, is found to lead to similar effects on smooth musculature and circulation as bradykinin.

Some ants are also rated at a Pain Level 3, including the giant bull ant and the Maricopa harvester ant. Schmidt considered the sting of the Maricopa harvester ant as having a pain level of 3, describing it as such: “After eight unrelenting hours of drilling into that ingrown toenail, you find the drill wedged into the toe.”

Pain Level 4
Pain Level 4 is the highest level in the Schmidt sting pain index. Schmidt gave the sting of the tarantula hawk a rating of a 4, which he described as "blinding, fierce [and] shockingly electric." The composition of the tarantula hawk sting is unknown, though the duration of the sting is short-lived, lasting only approximately 5 minutes.

Schmidt rated the sting of the bullet ant as a 4-plus. This sting can last between 5 to 24 hours. Schmidt has described the sting as "pure, intense, brilliant pain...like walking over flaming charcoal with a three-inch nail embedded in your heel." The bullet ant's venom primarily contains poneratoxin, a paralyzing neurotoxic peptide.

Schmidt has considered the stings of the tarantula hawk and the bullet ant to be the most painful stings.

= Poneratoxin =

Biological Mechanism
Overall, poneratoxin disrupts normal function of voltage-gated sodium channels in both vertebrates and invertebrates. It causes repetitive firing and prolongation of action potentials, particularly in the central nervous system of insects. The increase in signaling is what causes the intense pain from bullet ant stings.

Poneratoxin is in an inactive state when stored in the ant venom reservoir due to the reservoir's acidic conditions, but it becomes toxic when activated via a multistep process. The combination of poneratoxin binding to a cell membrane (in order to act upon a voltage-gated sodium channel) and the movement from acidic conditions in the ant venom reservoir to basic conditions at the target site leads to poneratoxin undergoing a conformational change that activates it.

Catterall et al. hypothesized that some polypeptide neurotoxins that modify voltage-gated channels function via a "voltage-sensor trapping" mechanism. The hypothesis states that neurotoxins similar to poneratoxin, such as alpha-scorpion toxins, act upon sodium channels via binding to the channels' receptor site 3, which normally affects the channels' ability to inactivate. Therefore, receptor site 3 neurotoxins often affect sodium channels by slowing or blocking inactivation. Normally, the region of the channel where neurotoxin receptor site 3 is undergoes a conformational change of an outward movement to lead to inactivation. Receptor site 3 neurotoxins are proposed to prevent this conformational change via interaction with acidic and hydrophobic amino acid residues at that site.

When frog skeletal muscle fibers were exposed to poneratoxin, it was found that poneratoxin primarily affected voltage-dependent sodium channels by decreasing the peak sodium current and also inducing a slow sodium current. This combination resulted in the sodium channels activating at very negative potentials and deactivating very slowly, a phenomenon commonly seen in excitable tissues. Poneratoxin is considered as a slow acting agonist for smooth muscles.

Toxicology
Many people consider a sting from a bullet ant to resemble the sensation of getting shot. Justin Schmidt, an entomologist who developed the Schmidt sting pain index, described it as "pure, intense, brilliant pain...like walking over flaming charcoal with a three-inch nail embedded in your heel," and considers the sting from a bullet ant to be the most painful insect sting he has experienced. The pain from bullet ant stings can last for many hours, even up to 24 hours. Both the immense pain and the duration of the sting are due to the effects of poneratoxin. In addition to the infamous pain, symptoms of stings from bullet ants (as well as stings from other ants of the genus Paraponera as well as the genus Dinoponera) include fever, cold sweats, nausea, vomiting, lymphadenopathy and cardiac arrhythmias.

Toxicity assays have found that the LT50 of poneratoxin, delivered via viral injections to S. frugiperda larvae, was at 131 hours post injection. A dose of 105 pfu of poneratoxin was sufficient to kill the S. frugiperda larvae, and a dose of 10 ng could paralyze them. Based on these experiments, scientists believe poneratoxin can make a good candidate as a bio-insecticide because of its neurotoxicity to other insects, making it capable of immobilizing or even killing insects infected with it. The thought is to make a recombinant virus by engineering a baculovirus that expresses poneratoxin. However, one of the major concerns with this idea is that the poneratoxin-expressing recombinant virus may be toxic to the environment because it is genetically modified.