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.