Localisation analysis of nerves in the mouse pancreas reveals the sites of highest nerve density and nociceptive innervation

• Published in: Neurogastroenterology and motility 2020-11, Vol.32 (11), p.e13880-n/a
• Main Authors: Saricaoglu, Ömer Cemil, Teller, Steffen, Wang, Xiaobo, Wang, Shenghan, Stupakov, Pavel, Heinrich, Tobias, Istvanffy, Rouzanna, Friess, Helmut, Ceyhan, Güralp O., Demir, Ihsan Ekin
• Format: Article
• Language: English
• Subjects: Anatomy; Animal models; BDNF; Blood vessels; Brain-derived neurotrophic factor; Colorimetry; Fibers; Immunohistochemistry; Innervation; mouse; nerve trunks; Nerves; Nervous system; Neurosciences; nitrergic; pain; Pain perception; Pancreas; Pancreatic cancer; Pancreatitis; Peripheral neuropathy; Sectioning
• ISSN: 1350-1925; 1365-2982
• DOI: 10.1111/nmo.13880

Background 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. Methods 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. Key Results 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. Conclusions & Inferences 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. Pancreatic cancer and chronic pancreatitis are characterized by a prominent pancreatic neuropathy and neuropathic pain. Mice are increasingly used for modelling neural alterations of pancreatic diseases; however, the numerous differences regarding the normal neuro‐anatomy and innervation between the mouse and human pancreas have so far been completely neglected. In the present study, we addressed this gap by introducing a standardized tissue harvesting and paraffin‐embedding technique that preserves the anatomical orientation of the mouse pancreas and allows complete sectioning in an anterior‐to‐posterior fashion. This way, we analysed the morphology ad distribution of nerve trunk