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The mechanism by which pancreatitis causes pain is unknown. The neuropeptide calcitonin gene–related peptide (CGRP) is released after sensory nerve activation and promotes nociceptive signaling in models of visceral pain. We hypothesized that acute pancreatitis leads to the activation of pancreatic sensory neurons that release CGRP in the dorsal horn of the spinal cord. This signal is ultimately transmitted to the brain, and pain is sensed.To induce pancreatitis, rats were injected with L-arginine (500 mg/kg) intraperitoneally or saline (control). Pancreatitis was confirmed by measuring serum amylase and evaluating pancreatic histology. Activation of nociceptive pathways was evaluated by counting Fos-like immunoreactive nuclei (FLI) in the dorsal horn of the spinal cord at T3-L1. Some animals received the CGRP antagonist CGRP8-37 (50 μg intrathecally) 2 hours before perfusion. Animals were compared using a 2-tailed t test.L-Arginine treatment induced acute necrotizing pancreatitis in the rat at 24 hours. L-Arginine (24 hours) increased FLI in the dorsal horn of the spinal cord, with a peak effect at L1. Intrathecal administration of CGRP8-37 significantly decreased the number of FLI nuclei in the dorsal horn of the spinal cord in T11-L1.Nociception in the L-arginine model of acute pancreatitis is partially mediated by the release of CGRP in the dorsal horn of the spinal cord. Antagonism of CGRP or its receptors may be useful in treating pain from acute pancreatitis.