A comparative anatomical and histological study on the presence of an apical splenic nerve in mice and humans.

The cranial pole of the mouse spleen is considered to be parasympathetically innervated by a macroscopic observable nerve referred to as the apical splenic nerve (ASN). Electrical stimulation of the ASN resulted in increased levels of splenic acetylcholine, decreased lipopolysaccharide-induced levels of systemic tumor necrosis factor alpha and mitigated clinical symptoms in a mouse model of rheumatoid arthritis. If such a discrete ASN would be present in humans, this structure is of interest as it might represent a relatively easily accessible electrical stimulation target to treat immune-mediated inflammatory diseases. So far, it is unknown if a human ASN equivalent exists. This study aimed to provide a detailed description of the location and course of the ASN in mice. Subsequently, this information was used for a guided exploration of an equivalent structure in humans. Microscopic techniques were applied to confirm nerve identity and compare ASN composition. Six mice and six human cadavers were used to study and compare the ASN, both macro- and microscopically. Macroscopic morphological characteristics of the ASN in both mice and humans were described and photographs were taken. ASN samples were resected, embedded in paraffin, cut in 5 µm thin sections where after adjacent sections were stained with a general, sympathetic and parasympathetic nerve marker, respectively. Neural identity and nerve fiber composition was then evaluated microscopically. Macroscopically, the ASN could be clearly identified in all mice and was running in the phrenicosplenic ligament connecting the diaphragm and apical pole of the spleen. If a phrenicosplenic ligament was present in humans, a similar configuration of potential neural structures was observed. Since the gastrosplenic ligament was a continuation of the phrenicosplenic ligament, this ligament was explored as well and contained white, potential discrete nerve-like structures as well which could represent an ANS equivalent. Microscopic evaluation of the ASN in mice and human showed that this structure did not represent a nerve, but most likely connective tissue strains. White nerve-like structures, which could represent the ASN, were macroscopically observed in the phrenicosplenic ligament in both mice and human and in the gastrosplenic ligament in humans. The microscopic investigation did not confirm their neural identity and therefore, this study disclaims the existence of a parasympathetic ASN in both mice and human.

Sensory Innervation of Human Bone: An Immunohistochemical Study to Further Understand Bone Pain.

Skeletal diseases and their surgical treatment induce severe pain. The innervation density of bone potentially explains the severe pain reported. Animal studies concluded that sensory myelinated A∂-fibers and unmyelinated C-fibers are mainly responsible for conducting bone pain, and that the innervation density of these nerve fibers was highest in periosteum. However, literature regarding sensory innervation of human bone is scarce. This observational study aimed to quantify sensory nerve fiber density in periosteum, cortical bone, and bone marrow of axial and appendicular human bones using immunohistochemistry and confocal microscopy. Multivariate Poisson regression analysis demonstrated that the total number of sensory and sympathetic nerve fibers was highest in periosteum, followed by bone marrow, and cortical bone for all bones studied. Bone from thoracic vertebral bodies contained most sensory nerve fibers, followed by the upper extremity, lower extremity, and parietal neurocranium. The number of nerve fibers declined with age and did not differ between male and female specimens. Sensory nerve fibers were organized as a branched network throughout the periosteum. The current results provide an explanation for the severe pain accompanying skeletal disease, fracture, or surgery. Further, the results could provide more insight into mechanisms that generate and maintain skeletal pain and might aid in developing new treatment strategies. PERSPECTIVE: This article presents the innervation of human bone and assesses the effect of age, gender, bone compartment and type of bone on innervation density. The presented data provide an explanation for the severity of bone pain arising from skeletal diseases and their surgical treatment.