{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T22:34:36Z","timestamp":1768516476046,"version":"3.49.0"},"posted":{"date-parts":[[2024,9,12]]},"group-title":"Neuroscience","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,12]],"date-time":"2024-09-12T00:00:00Z","timestamp":1726099200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,12]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Evolutionary arms races between predator and prey can lead to extremely specific and effective defense mechanisms. Such defenses include venoms that deter predators by targeting nociceptive (pain-sensing) pathways. Through co-evolution, venom toxins can become extremely efficient modulators of their molecular targets. The venom of velvet ants (Hymenoptera: Mutillidae) is notoriously painful. The intensity of a velvet ant sting has been described as \u201cExplosive and long lasting, you sound insane as you scream. Hot oil from the deep fryer spilling over your entire hand.\u201d [1] The effectiveness of the velvet ant sting as a deterrent against potential predators has been shown across vertebrate orders, including mammals, amphibians, reptiles, and birds [2\u20134]. The venom\u2019s low toxicity suggests it has a targeted effect on nociceptive sensory mechanisms [5]. This leads to the hypothesis that velvet ant venom targets a conserved nociception mechanism, which we sought to uncover using\n                  <jats:italic>Drosophila melanogaster<\/jats:italic>\n                  as a model system.\n                  <jats:italic>Drosophila<\/jats:italic>\n                  larvae have peripheral sensory neurons that sense potentially damaging (noxious) stimuli such as high temperature, harsh mechanical touch, and noxious chemicals [6\u20139]. These polymodal nociceptors are called class IV multidendritic dendritic arborizing (cIV da) neurons, and they share many features with vertebrate nociceptors, including conserved sensory receptor channels [10,11]. We found that velvet ant venom strongly activated\n                  <jats:italic>Drosophila<\/jats:italic>\n                  nociceptors through heteromeric Pickpocket\/Balboa (Ppk\/Bba) ion channels. Furthermore, we found a single venom peptide (Do6a) that activated larval nociceptors at nanomolar concentrations through Ppk\/Bba.\n                  <jats:italic>Drosophila<\/jats:italic>\n                  Ppk\/Bba is homologous to mammalian Acid Sensing Ion Channels (ASICs) [12]. However, the Do6a peptide did not produce behavioral signs of nociception in mice, which was instead triggered by other non-specific, less potent, peptides within the venom. This suggests that Do6a is an insect-specific venom component that potently activates insect nociceptors. Consistent with this, we showed that the velvet ant\u2019s defensive sting produced aversive behavior in a predatory praying mantis. Together, our results indicate that velvet ant venom evolved to target nociceptive systems of both vertebrates and invertebrates, but through different molecular mechanisms.\n                <\/jats:p>","DOI":"10.1101\/2024.09.12.612741","type":"posted-content","created":{"date-parts":[[2024,9,12]],"date-time":"2024-09-12T21:50:50Z","timestamp":1726177850000},"source":"Crossref","is-referenced-by-count":0,"title":["Multiple mechanisms of action of an extremely painful venom"],"prefix":"10.64898","author":[{"given":"Lydia J.","family":"Borjon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luana C.","family":"de Assis Ferreira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan C.","family":"Trinidad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sun\u010dica","family":"\u0160a\u0161i\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea G.","family":"Hohmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. Daniel","family":"Tracey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024091522295642000_2024.09.12.612741v1.1","unstructured":"Schmidt JO . The sting of the wild. 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