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Spatiotemporal dynamics of re-innervation and hyperinnervation patterns by uninjured CGRP fibers in the rat foot sole epidermis after nerve injury

Liron S Duraku12*, Mehdi Hossaini1, Sieske Hoendervangers2, Lukas L Falke2, Shoista Kambiz12, Vivek C Mudera3, Joan C Holstege1, Erik T Walbeehm2 and Tom J H Ruigrok1

Author Affiliations

1 Department of Neuroscience, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

2 Department of Plastic, Reconstructive and Hand Surgery, Erasmus MC, University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands

3 The Institute of Orthopedics and Musculoskeletal Sciences, Royal National Orthopedic Hospital, University College London, Stanmore, UK

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Molecular Pain 2012, 8:61  doi:10.1186/1744-8069-8-61

Published: 30 August 2012


The epidermis is innervated by fine nerve endings that are important in mediating nociceptive stimuli. However, their precise role in neuropathic pain is still controversial. Here, we have studied the role of epidermal peptidergic nociceptive fibers that are located adjacent to injured fibers in a rat model of neuropathic pain. Using the Spared Nerve Injury (SNI) model, which involves complete transections of the tibial and common peroneal nerve while sparing the sural and saphenous branches, mechanical hypersensitivity was induced of the uninjured lateral (sural) and medial (saphenous) area of the foot sole. At different time points, a complete foot sole biopsy was taken from the injured paw and processed for Calcitonin Gene-Related Peptide (CGRP) immunohistochemistry. Subsequently, a novel 2D-reconstruction model depicting the density of CGRP fibers was made to evaluate the course of denervation and re-innervation by uninjured CGRP fibers. The results show an increased density of uninjured CGRP-IR epidermal fibers on the lateral and medial side after a SNI procedure at 5 and 10 weeks. Furthermore, although in control animals the density of epidermal CGRP-IR fibers in the footpads was lower compared to the surrounding skin of the foot, 10 weeks after the SNI procedure, the initially denervated footpads displayed a hyper-innervation. These data support the idea that uninjured fibers may play a considerable role in development and maintenance of neuropathic pain and that it is important to take larger biopsies to test the relationship between innervation of injured and uninjured nerve areas.

SNI; PGP 9.5; CGRP; Substance P; NF-200; P2X3; Epidermis