The cytoplasmic protein gene product 9.5 (PGP 9.5) is considered a reliable marker for intraepidermal nerve fibers (IENFs). However, PGP 9.5 expression has never been compared with antibodies against the main components of the cytoskeleton. We compared the density of PGP 9.5-positive IENF at the leg with that obtained using a panel of antibodies specific for certain cytoskeletal components, namely, anti-unique beta-tubulin (TuJ1), anti-nonphosphorylated microtubule-associated protein-1B (MAP1B), anti-70 and 200 KDa neurofilament (NF), and antiphosphorylated neurofilament (SMI 312), in 15 healthy subjects and in 10 patients with painful neuropathy. We also performed colocalization studies and investigated the relationship between IENFs and Schwann cells. In both controls and neuropathies, the density of IENF labeled by PGP 9.5, TuJ1, and MAP1B did not differ, whereas that of NF and SMI 312 was significantly lower. Double-staining studies confirmed that antibodies against cytoskeletal markers can be used to reliably stain skin nerve fibers, suggesting that they might provide insight into specific axonal impairment in peripheral neuropathies.
"However, the most intriguing and challenging question remained whether changes in IENF density could correlate with positive sensory symptoms. Some key characteristics of IENF, such as the lack of Schwann cell membrane  and the extensive expression of transient receptor potential vanilloid type 1 , along with the role of resident epidermal cells in the transduction of somatosensation , suggest that the entire skin, rather than nerve fibers alone, is a complex polymodal receptor in which axon-cell networks contribute in the generation of thermal and nociceptive sensation and, possibly, neuropathic pain. "
"In sham-treated rats, we found NF-200-IF fibers in bundles located throughout the upper dermis without any NF-200-IR fibers penetrating the epidermis (Figs. 4E and 7A) in accordance with previous reports (Lauria et al., 2004; Peleshok and Ribeiro-da-Silva, 2011). No significant differences were found in NF-200-IR fiber densities between footpad and non-footpads areas (Fig. 4F). "
[Show abstract][Hide abstract] ABSTRACT: Nerve endings in the epidermis, termed nociceptors, conduct information on noxious stimuli to the central nervous system. The precise role of epidermal nerve fibers in neuropathic pain is however still controversial. Here, we have investigated the re-innervation patterns of epidermal and dermal nerve fibers in a rat neuropathic pain model. After applying the spared nerve injury (SNI) model, we determined the mechanical and thermal withdrawal thresholds in the uninjured lateral (sural) and medial (saphenous) areas of the affected hind paw and investigated the innervations patterns of Substance P (SubP), Neurofilament-200 (NF-200) and P2X3-immunoreactive (IR) nerve fibers in the epidermis and dermis. We found a significant loss in the density of peptidergic (Sub P and NF-200) and non-peptidergic (P2X3) nerve fibers in the center area of the foot sole at 2 weeks postoperatively (PO). The densities of Sub P-IR fibers in the epidermis and upper dermis, and the density of P2X3-IR fibers in the upper dermis were significantly increased at 10 weeks PO as compared to 2 weeks PO, but were still significantly lower than the densities in controls. However, the density of NF-200-IR fibers in the center area reached control levels at 10 weeks PO. No changes were found in the densities of any of the fibers in the medial and lateral parts of the foot sole. The present results suggest that after peripheral nerve injury, specific nerve fibers have different re-innervation patterns in the epidermis and dermis and that they might be involved in the development of neuropathic pain.
"IENF are somatic axons which lose the Schwann cell ensheathment while crossing the dermalepidermal barrier, as demonstrated by ultrastructural and immunohistochemical studies (Hilliges et al., 1995; Lauria et al., 2004). They are the terminal endings of small neurons of dorsal root ganglia (DRG) and widely express the capsaicin receptor (Lauria et al., 2006). "
[Show abstract][Hide abstract] ABSTRACT: Starting from the original studies of the 19th century, this review covers some of the advances achieved over the last 15 years since skin biopsy has become a diagnostic tool for neurologists. In a relatively short period of time, focused works demonstrated the correlation between the loss of intraepidermal nerve fibers (IENF) and symptoms and signs of small fiber neuropathy (SFN), and provided standardized protocols for nerve morphometry as well as normative reference values to be used in clinical practice. This contributed to the definition of the diagnostic criteria for SFN that is now recognized as a distinct nosologic entity. The relationship between IENF degeneration and neuropathic pain led to the recent discovery that SFN can be caused by mutations in sodium channels, providing evidence for a new diagnostic approach to the etiology of the disease in patients. The presence of myelinated nerve fibers in the dermis prompted studies focused on demyelinating neuropathies of genetic and immune-mediated origin. Specific changes in dermal myelinated nerves have been described suggesting a potential role for skin biopsy also in these fields. Finally, studies on the sequence of events occurring after nerve degeneration in experimental models and patients with chronic neuropathies allowed to understand better the ability of skin nerves to regenerate and the reasons for its failure, providing important hints for the use of skin biopsy as an outcome measure in clinical practice and neuroprotective trials.
Journal of the Peripheral Nervous System 12/2012; 17 Suppl 3(s3):38-45. DOI:10.1111/j.1529-8027.2012.00430.x · 2.76 Impact Factor
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