Neurexin regulates mechanical nociceptive sensitization by central inhibition in <i>Drosophila</i>

Synaptic adhesion molecules play a crucial role in shaping neural circuits and behavior, yet their contribution to nociceptive processing remains poorly understood. Here, we investigate how the synaptic organizer Neurexin regulates mechanical nociception in <i>Drosophila</i> larvae. Using genetic, behavioral, and circuit-level analyses, we demonstrate that loss of <i>neurexin</i> induces mechanical nociceptive sensitization, which depends on a specific cluster of central cholinergic neurons in the subesophageal zone. These neurons drive sensitization through a C4da-Goro circuit, where Neurexin modulates presynaptic GABA_B receptor signaling to control nociceptive excitability. Our findings establish Neurexin as a key of nociceptive sensitization and uncover a synaptic mechanism for tuning nociceptive thresholds, with implications for understanding chronic pain and sensory circuit dysfunctions in neurodevelopmental disorders.