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2007 Program and Abstracts | 2007 Posters
Nerve Growth Factor Mediates Pancreatic Inflammatory Pain Via PKC-Dependent Signaling of TRPV1
Eugene P. Ceppa*1, Sarah Grahn2, Lorna Divino2, Eileen F. Grady2, Kimberly S. Kirkwood2
1Surgery, Duke University Medical Center, Durham, NC; 2Surgery, University of California, San Francisco, San Francisco, CA

Introduction
Pain is the cardinal symptom of acute pancreatitis, however the pathophysiology of pancreatic inflammatory pain remains unclear. Nerve growth factor (NGF) mediates visceral pain in experimental models of cystitis and colitis. Increase in NGF release occurs within 2h of the onset of L-Arg pancreatitis followed by increases in mRNA and protein expression. We hypothesized that (1) intrapancreatic NGF would induce pancreatic inflammation and activate pancreatic pain pathways via activation of the NGF receptor TrkA, (2) this response would involve PKC-mediated activation of TRPV1, and (3) pretreatment with a trkA receptor blocker would decrease cerulein pancreatitis - induced inflammation and pain.
Methods
Animals were pre-treated with either TrkA receptor antagonist K252a (0.05µg/kg pancreatic duct), PKC antagonist GFX (0.04mg/kg pancreatic duct), TRPV1 antagonist capsazepine (1.8mg/kg intraperitoneal, CPZ) or respective vehicles. NGF (250μls, 8µg/ml over 10min) or vehicle was injected into pancreatic duct of anesthetized rats. After 2.5h, pancreatic, serum, and spinal cord samples were removed and the following endpoints were measured: pancreatic inflammation (serum amylase, histology severity score, and pancreas MPO activity) and pain (spinal cord fos expression in the dorsal horn at T8-10 with T6 and T12 as internal controls). Animals were pre-treated with anti-NGF Ab (500μls [1/2000], 2ml/kg, intraperitoneal), K252a (250μls, 0.05µg/kg, intraperitoneal), or vehicle prior to induction of cerulein pancreatitis (200µg/kg/sc/h for 4h). Tissue samples were collected at 6h.
Results and Conclusions
Pretreatment of animals with K252a, GFX, and CPZ had no effect on any of the indices of inflammation. However, all three inhibitors significantly reduced the number of fos positive neurons at T8-T10 as compared to NGF alone group (fos positive nuclei: Veh/NGF, 36±4; K252a/NGF, *18±1; GFX/NGF, *21±2; CPZ/NGF, *17±1 (*p<0.05 compared to Veh/NGF)). The effect was specific to the pancreas since no differences existed at T6 and T12. Nociception was due to TrkA activation since it was inhibited by K252a, occurred via a PKC dependent pathway (inhibited by GFX), and due to activation of TRPV1 (inhibited by CPZ). Pretreatment of animals with anti-NGF antibody or K252a significantly reduced both serum amylase activity and pain due to cerulein pancreatitis (fos positive nuclei: Veh/Cerulein, 9±1; aNGF/Cerulein *3±1; K252a/Cerulein, *6±1; (*p<0.05 compared to Veh/Cerulein)). We conclude that NGF, which is released early in the course of acute pancreatitis, may play an important role in promoting pancreatic inflammatory pain via PKC-mediated activation of TRPV1.


2007 Program and Abstracts | 2007 Posters
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