Abstract
Neuropathy and neuro-inflammation drive the severe pain and disease progression in human chronic pancreatitis and pancreatic cancer. Mice, especially genetically induced-mouse models, have been increasingly utilized in mechanistic research on pancreatic neuropathy, but the normal "peripheral neurobiology" of the mouse pancreas has not yet been critically compared to human pancreas. We introduced a standardized tissue-harvesting technique that preserves the anatomic orientation of the mouse pancreas and allows complete sectioning in an anterior to posterior fashion. We applied immunohistochemistry and quantitative colorimetry of all nerves from the whole organ for studying pancreatic neuro-anatomy. Nerves in the mouse pancreas appeared as "clusters" of nerve trunks in contrast to singly distributed nerve trunks in the human pancreas. Nerve trunks in the mouse pancreas were exclusively found around intrapancreatic blood vessels, and around lymphoid structures. The majority of nerve trunks were located in the pancreatic head (0.15±0.08% of tissue area) and the anterior/front surface of the corpus/body (0.17±0.27%), thus significantly more than in the tail (0.02±0.02%, P=.006). Nerves in the tail included a higher proportion of nociceptive fibers, but the absolute majority, ie, ca. 70%, of all nociceptive fibers, were localized in the head. Mice heterozygous for Bdnf knockout allele (Bdnf+/- ) exhibited enrichment of nitrergic nerve fibers specifically in the head and corpus. Neuro-anatomy of the "mesenteric type" mouse pancreas is highly different from the "compact" human pancreas. Studies that aim at reproducing human pancreatic neuro-phenomena in mouse models should pay diligent attention to these anatomic differences.
Highlights
Pancreatic cancer (PCa) and chronic pancreatitis (CP) are characterized by prominent alterations of intrapancreatic nerves like nerve hypertrophy, neuro-inflammation, and neural invasion, which are to give rise to severe neuropathic abdominal pain.[1,2,3] Mouse models, genetically induced mouse models, have been recently and increasingly introduced into the study of these neuropathic alterations.[4,5,6] these studies do not yet seem to take into account sufficiently the anatomic differences in the innervation of the mouse pancreas vs human pancreas
Among pain-transmitting nerve fiber subtypes, we show that the distribution of nerves which contain pain-related neuropeptides like substance P (SP), CGRP, vasoactive intestinal peptide (VIP), or NOS, does not vary between different regions of the mouse pancreas and that they constitute around 10% percent of the total innervation
We looked at the amount of VIP+ or nitrergic, that is, neuronal nitric oxide synthase (nNOS)-containing nerve fibers in the normal mouse pancreas (Figure 4A) and compared these amounts to mice that were heterozygously knocked out for brain-derived neurotrophic factor (BDNF, here termed the Bdnf+/− mice), since homozygous Bdnf −/− mice are hardly alive until the adult age.[12]
Summary
Pancreatic cancer (PCa) and chronic pancreatitis (CP) are characterized by prominent alterations of intrapancreatic nerves like nerve hypertrophy, neuro-inflammation, and neural invasion, which are to give rise to severe neuropathic abdominal pain.[1,2,3] Mouse models, genetically induced mouse models, have been recently and increasingly introduced into the study of these neuropathic alterations.[4,5,6] these studies do not yet seem to take into account sufficiently the anatomic differences in the innervation of the mouse pancreas vs human pancreas. To date, despite some studies that compared the ganglia and the fine nerve fiber distribution,[8,9] there has been no study that investigated the differences in the nerve trunk anatomy between the mouse and the human pancreas. We show that mouse pancreatic nerve trunks are solely located around peripancreatic lymphoid structures and around vascular complexes. Among pain-transmitting nerve fiber subtypes, we show that the distribution of nerves which contain pain-related neuropeptides like substance P (SP), CGRP, vasoactive intestinal peptide (VIP), or NOS, does not vary between different regions of the mouse pancreas and that they constitute around 10% percent of the total innervation. Our study provides a reference for studying the mouse pancreatic innervation within the frame of morphological, anatomic, mechanistic, or neurochemical code studies
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