Re-innervation patterns by peptidergic Substance-P, non-peptidergic P2X3, and myelinated NF-200 nerve fibers in epidermis and dermis of rats with neuropathic pain

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 2weeks 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 10weeks PO as compared to 2weeks 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 10weeks 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. ► Spared nerve injury was used to induce denervation of part of the rat hind paw. ► Outgrowth of uninjured Substance P, P2X3 and NF-200 fibers was studied. ► P2X3 and Substance P fibers cause only partial re-innervation of denervated skin. ► A complete re-innervation is found by uninjured NF-200 fibers in the skin. ► Results were also compared with earlier obtained changes of CGRP containing fibers.