Nerve injury drives a heightened state of vigilance and neuropathic sensitization in Drosophila.

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 nAChRα1 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 conserved transcription factor twist as a critical downstream regulator driving GABAergic cell death and neuropathic allodynia. Together, we define how injury leads to allodynia in insects, and describe a primordial precursor to neuropathic pain may have been advantageous, protecting animals after serious injury.