The vagus nerve activated by inflammation co-transmits acute visceral pain via the NTS-PVN pathway

• A vagus-dependent pancreas-brain axis for inflammatory visceral pain is identified: TNF-α associated with acute pancreatitis sensitizes TRPV1 + vagal neurons and activates the NTS → PVN pathway. • Dual peripheral intervention strategies: Vagotomy (VGX) and nodose ganglion (NG) TRPV1 + neuron ablation (via RTX) both partially alleviate acute pancreatitis-induced pain, validating the vagus nerve as a critical pain conduit. • Central circuit-specific modulation: Chemogenetic or optogenetic inhibition of the NTS Glu → PVN Glu pathway attenuates visceral pain behaviors. Acute pancreatitis (AP) induces visceral pain through inflammation and mechanical stress, yet current treatments remain inadequate. This therapeutic limitation reflects our limited knowledge of how nociceptive signals are transmitted from peripheral visceral afferents to central neural pathways. A neural circuit connecting the pancreas and the brain was mapped using various viral tracer techniques. The role of this circuit in acute pancreatitis-induced visceral pain was verified using optogenetics, chemogenetics, fiber-optic in vivo calcium signal recording, and electrophysiological techniques. AP-associated elevation of the inflammatory cytokine TNF-α sensitizes transient receptor potential vanilloid 1-positive (TRPV1 + ) neurons in the nodose ganglia (NG) of the vagus nerve. Both bilateral subdiaphragmatic vagotomy (VGX) and NG resiniferatoxin (RTX) injection partially alleviated acute pancreatitis (AP)-induced visceral pain. In the brain, glutamatergic neurons in the nucleus tractus solitarius (NTS) receive projections from AP-activated NG TRPV1 neurons, subsequently transmitting pain signals to the glutamatergic neurons in paraventricular nucleus of hypothalamus (PVN). Chemogenetic or optogenetic inhibition of the NTS Glu → PVN Glu pathway effectively alleviates AP-induced visceral pain behaviors in mice. Our study structurally identified a vagus nerve-mediated pancreas-brain axis (pancreas → NG TRPV1 → NTS Glu → PVN Glu ) that co-transmits inflammatory cytokine-activated visceral pain signals alongside spinal pathways.