Mechanisms of Pancreatitis-induced Pain

Abstract

Pathogenesis of pain in pancreatitis is multifactorial, however little is known about the mechanisms by which inflammation in the pancreas causes pain. Here, we hypothesized that pancreatitis-induced pain is dependent upon sensitization of primary afferents by inflammatory mediators such as nerve growth factor (NGF) and interleukin-6(IL-6) and that such a pain is mediated through ascending pathways via the nucleus gracilis. Inflammation in the pancreas resulted in a significant increase in the levels of NGF in the pancreas. Pre-treatment with an anti-NGF peptibody delayed the development of pancreatitis-induced pain. Double injection of anti-NGF peptibody completely prevented the development of pancreatitis-induced pain. Post-treatment with anti-NGF peptibody significantly decreased the number of abdominal withdrawals, compared to the placebo group. Treatment with TRPV1 antagonists reversed the referred abdominal hypersensitivity. Intrathecal administration of p38 inhibitor blocked the pancreatitis-induced pain within minutes after administration. The levels of the TRPV1 in the pancreas, DRG and the spinal cord were not significantly different in the animals with pancreatitis compared to the controls. Pancreatic inflammation resulted in a significant increase in the levels of IL-6 in the pancreas. Treatment with an IL-6 receptor antagonist blocked the referred abdominal hypersensitivity in animals with pancreatitis after systemic and oral administration. Intrathecal administration of the antagonist did not reduce the number of abdominal withdrawals. The possibility that IL-6 might sensitize TRPV1 channels was tested. Cultured DRG neurons were stimulated with IL-6, IL-6 antagonist or a combination of IL-6 with an antagonist, followed by stimulation with capsaicin. Stimulation of DRG with IL-6 produced a marked increase in the levels of CGRP release; combination of IL-6 with an antagonist returned the levels of CGRP to the control levels. To determine the role of the nucleus gracilis in the pancreatitis-induced pain bilateral cannulation of the nucleus gracilis was performed. Microinjection of CNQX into the nucleus gracilis produced a reversal of pancreatitis-induced pain, suggesting an important role of ascending pathway to the n.gracilis in pancreatic pain transmission.