Altered Pancreatic Innervation Linked to Changes in Pain-Related Behavior

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(ChemotherapyAdvisor) – A transgenic mouse model of pancreatic cancer has found that significant changes in pancreatic innervation and neurotrophic factor expression can be correlated with pain-related decreases in ambulatory and reaching activity, a study presented June 19 at the American Association for Cancer Research's Pancreatic Cancer: Progress and Challenges conference, Lake Tahoe, NV, has found.

These results will enable systematic study of the effect of neuroplastic changes in the pancreatic ductal adenocarcinoma (PDAC) microenvironment on development of pancreatic cancer-related pain, noted Rachelle E. Stopczynski, an MD/PhD student at the University of Pittsburgh, Pittsburgh, PA.

The investigators hypothesized that neurotrophic factors—including nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), GDNF family member artemin (Artn), and brain-derived neurotrophic factor (BDNF)—would increase in the pancreas of PDAC mice as the tumors develop, “leading to altered pancreatic innervation and changes in pain-related behavior.”

Pancreas RNA was isolated from PDAC mice and controls at 16 to 30 weeks of age and levels of neurotrophic factor and neurotrophic factor receptor mRNA expression measured using PCR and qRT-PCR. Compared with control mice, expression of NGF, the NGF receptor TrkA, Artn, GDNF, the GDNF receptor GFRa1, BDNF, and the BDNF receptor TrkB were increased in the pancreas of PDAC mice, they found.

In addition, large nerve bundles that stained intensely with the pan-neuronal marker PGP 9.5, tyrosine hydroxylase (TH; NGF-responsive sympathetic fibers), calcitonin gene-related peptide (CGRP; sensory fibers), and growth-associated protein 43 (GAP-43; nerve sprouting) were observed in the pancreas of PDAC mice but not in controls.

When the exploratory behavior of PDAC mice was examined, they were found to spend “less time moving horizontally and vertically, had a reduced number of reaching movements into the vertical plane, traveled less distance in the vertical plane, and made fewer movements in the vertical plane,” Stopczynski said.

Morbidity in PDAC is partly due to the severe pain reported by patients with the disease. “Tumor-nerve interactions including intrapancreatic perineural invasion, neurogenic inflammation, and neuritis are key features of pancreatic malignancies and are thought to play an important role in pancreatic cancer-related pain,” she reported.

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