Excessive-ramification and sprouting of intra-pancreatic sensory nerve-fibers in the chronic pancreatitis model.

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Increase in number of intrapancreatic nerve bundles has been implicated in the generation of persistent pain in chronic pancreatitis. To examine the origin of these nerve fibers and the mechanisms linking neural morphological change to pain generation, we used neuronal tracing techniques in combination with immunohistochemistry in spontaneous chronic pancreatitis in the WBN/Kob rats.For retrograde tracing, horseradish peroxidase (HRP) was injected into the pancreas, and labeled neurons in the sensory ganglia were counted. For anterograde tracing, biotinylated dextran amine (BDA) was injected into the dorsal root ganglia (DRGs), and labeled intrapancreatic sensory fibers were histochemically assessed. For assessment of pain generation, we evaluated c-Fos-positive neurons in the spinal dorsal horn and behavioral changes of the animals.In WBN/Kob rats, numbers of HRP-labeled neurons were decreased in the DRGs, and numbers of BDA-labeled intrapancreatic nerve fibers and terminals were increased. BDA-labeled nerve fibers contained growth-associated protein-43 (GAP-43). The number of c-Fos-positive neurons in the dorsal horn was also increased and was correlated with intrapancreatic GAP-43-immunoreactivity. Grooming behavior was reduced in WBN/Kob rats and this reduction was facilitated by exocrine stimulation. Axonal branching in DRG neurons innervating the pancreas increases in WBN/Kob rats ; and these morphological changes are likely involved in pain generation in chronic pancreatitis.