ABSTRACTEarly phase diabetes is often accompanied by pain sensitization. InDrosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. WhetherDrosophila InRalso regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the insulin receptor (Insr) show normal nociceptive baselines; however, it is uncertain whether deletion ofInsrin nociceptive sensory neurons leads to persistent nociceptive hypersensitivity. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies,InRmutants and larvae with sensory neuron-specific expression of RNAi transgenes targetingInRexhibited persistent mechanical hypersensitivity. Mice with a specific deletion of theInsrgene in Nav1.8+nociceptive sensory neurons showed nociceptive thermal and mechanical baselines similar to controls. In an inflammatory paradigm, however, these mutant mice showed persistent mechanical (but not thermal) hypersensitivity, particularly in female mice. Mice with the Nav1.8+sensory neuron-specific deletion ofInsrdid not show metabolic abnormalities typical of a defect in systemic insulin signaling. Our results show that some aspects of the regulation of nociceptive hypersensitivity by the insulin receptor are shared between flies and mice and that this regulation is likely independent of metabolic effects.