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Evolutionary arms races can lead to extremely specific and effective defense mechanisms, including venoms that deter predators by targeting nociceptive (pain-sensing) pathways. The venom of velvet ants (Hymenoptera: Mutillidae) is notoriously painful. It has been described as "Explosive and long lasting, you sound insane as you scream. Hot oil from the deep fryer spilling over your entire hand." 1 The effectiveness of the velvet ant sting against potential predators has been shown across vertebrate orders, including mammals, amphibians, reptiles, and birds. 2 , 3 , 4 This leads to the hypothesis that velvet ant venom targets a conserved nociception mechanism, which we sought to uncover using Drosophila melanogaster as a model system. Drosophila larvae have peripheral sensory neurons that sense potentially damaging (noxious) stimuli such as high temperature, harsh mechanical touch, and noxious chemicals. 5 , 6 , 7 , 8 They share features with vertebrate nociceptors, including conserved sensory receptor channels. 9 , 10 We found that velvet ant venom strongly activated Drosophila nociceptors through heteromeric Pickpocket/Balboa (Ppk/Bba) ion channels, through a single venom peptide, Do6a. Drosophila Ppk/Bba is homologous to mammalian acid-sensing ion channels (ASICs). 11 However, Do6a did not produce behavioral signs of nociception in mice, which was instead triggered by other venom peptides that are non-specific and less potent on Drosophila nociceptors. This suggests that Do6a has an insect-specific function. In fact, we further demonstrated that the velvet ant's sting produced aversive behavior in a predatory praying mantis. Together, our results indicate that velvet ant venom acts through different molecular mechanisms in vertebrates and invertebrates., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)