Increased cutaneous NGF and CGRP-labelled trkA-positive intra-epidermal nerve fibres in rat diabetic skin.

In this study we have determined the amount of Nerve Growth Factor (NGF) and the innervation density of the glabrous hindpaw skin of diabetic rats (n=4) and controls (n=3). The proportion of intra-epidermal nerve fibres (IENF) expressing the high affinity NGF receptor (trkA) and calcitonin gene-related peptide (CGRP) were also determined. Four weeks after induction of diabetes by intraperitoneal streptozotocin injection skin was analyzed for: (i) NGF content using ELISA and (ii) the innervation density of peptidergic afferents that also expressed trkA using immunocytochemistry. NGF levels were approximately three-fold higher in diabetic skin compared to controls (diabetic: 134.7±24.0 (SD) pgml(-1), control: 42.7±21.5pgml(-1), p=0.002). As expected there was a significant reduction in IENF density in diabetic skin (2.7±1.3 fibresmm(-1)) compared to controls (6.9±1.5 fibresmm(-1); p=0.01). In diabetic rats there was no significant difference in the proportion of trkA-labelled IENF (diabetic 74±21%; control 83±15%, p=0.6), but significantly more trkA-positive IENF were also labelled by CGRP antibodies in diabetic skin compared to controls (diabetic 89±22%; control 38±2%, p=0.03). These data suggest that in diabetes the upregulation of cutaneous NGF may 'over-troph' the surviving axons, increasing CGRP labelling, which may be important in the aetiology of painful diabetic neuropathy.