The Insulin receptor regulates the persistence of mechanical nociceptive sensitization in flies and mice

AbstractEarly phase diabetes is often accompanied by pain sensitization. In the fruit flyDrosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. WhetherDrosophilaInR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the gene encoding the Insulin receptor (Insr) show normal nociceptive baselines, however, it is not known whether deletion ofInsrin nociceptive sensory neurons leads to persistent nociceptive hypersensitivity in an inflammatory pain paradigm. 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, as previously observed for the thermal sensory modality. Mice with a specific deletion of theInsrgene in NaV1.8+ nociceptive sensory neurons showed normal 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 that would be typical of a systemic defect in 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.