biostudies-literatureKhuong TMNHMRCeaaw4099https://www.ebi.ac.uk/biostudies/studies/S-EPMC6620091biostudies-literatureUnknown5(7)Injury can lead to devastating and often untreatable chronic pain. While acute pain perception (nociception) evolved more than 500 million years ago, virtually nothing is known about the molecular origin of chronic pain. Here we provide the first evidence that nerve injury leads to chronic neuropathic sensitization in insects. Mechanistically, peripheral nerve injury triggers a loss of central inhibition that drives escape circuit plasticity and neuropathic allodynia. At the molecular level, excitotoxic signaling within GABAergic (γ-aminobutyric acid) neurons required the acetylcholine receptor <i>nAChRα1</i> and led to caspase-dependent death of GABAergic neurons. Conversely, disruption of GABA signaling was sufficient to trigger allodynia without injury. Last, we identified the conservedScience advancesNerve injury drives a heightened state of vigilance and neuropathic sensitization in <i>Drosophila</i>.PMC6620091CDF1111940APP1029672APP1046090APP1026310APP1086851APP1028887APP1042416Neely GGLau MTWang QPOyston LJTowler HLin YQKhuong TMManion JfalseNerve injury drives a heightened state of vigilance and neuropathic sensitization in <i>Drosophila</i>.Injury can lead to devastating and often untreatable chronic pain. While acute pain perception (nociception) evolved more than 500 million years ago, virtually nothing is known about the molecular origin of chronic pain. Here we provide the first evidence that nerve injury leads to chronic neuropathic sensitization in insects. Mechanistically, peripheral nerve injury triggers a loss of central inhibition that drives escape circuit plasticity and neuropathic allodynia. At the molecular level, excitotoxic signaling within GABAergic (γ-aminobutyric acid) neurons required the acetylcholine receptor <i>nAChRα1</i> and led to caspase-dependent death of GABAergic neurons. Conversely, disruption of GABA signaling was sufficient to trigger allodynia without injury. Last, we identified the conserved2019-01-01T00:00:00Z2019 Jul2025-04-22T15:45:59.106Z2019-07-25T07:07:28ZS-EPMC66200913130914810.1126/sciadv.aaw4099