Dissociation of thermal hypoalgesia and epidermal denervation in streptozotocin-diabetic mice

Abstract

The quantification of epidermal innervation, which consists primarily of heat-sensitive C-fibers, is emerging as a tool for diagnosing and staging diabetic neuropathy. However, the relationship between changes in heat sensitivity and changes in epidermal innervation has not yet been adequately explored. Therefore, we assessed epidermal nerve fiber density and thermal withdrawal latency in the hind paw of Swiss Webster mice after 2 and 4 weeks of streptozotocin-induced diabetes. Thermal hypoalgesia developed after only 2 weeks of diabetes, but a measurable reduction in PGP9.5-immunoreactive epidermal nerve fiber density did not appear until 4 weeks. These data suggest that impaired epidermal nociceptor function contributes to early diabetes-induced thermal hypoalgesia prior to the loss of peripheral terminals.

Figure 1

PGP9.5-immunostained epidermal (circles) and sub-epidermal (arrows) nerve fiber profiles in glabrous skin from the hind paw of control (A) and diabetic mice after 2 (B) or 4 (C) weeks of diabetes. GAP-43-immunostained epidermal and sub-epidermal nerve profiles in a diabetic mouse after 2 weeks of diabetes (D). Bar = 40 microns.

Figure 2. The Impact of Two Weeks of Diabetes

Paw thermal withdrawal latency (A), PGP9.5-immunoreactive IENF profile counts normalized to epidermal length (B) or epidermal area (C), epidermal thickness (D), a plot of paw thermal withdrawal latency against immunoreactive profile linear density (E) and sub-epidermal immunoreactive profile linear densities (F) for control and diabetic mice after 2 weeks of diabetes. Bar graphs show mean + SEM and were analyzed by unpaired t-test, ***p<0.001, *p<0.05. In the linear regression analysis, closed circles represent diabetic mice and open circles control mice.

Figure 3. The Impact of Four Weeks of Diabetes

Paw thermal withdrawal latency (A), PGP9.5-immunoreactive IENF profile counts normalized to epidermal length (B) or epidermal area (C), epidermal thickness (D), a plot of paw thermal withdrawal latency against immunoreactive profile linear density (E) and sub-epidermal immunoreactive profile linear densities (F) for control and diabetic mice after 4 weeks of diabetes. Bar graphs show mean + SEM and were analyzed by unpaired t-test, **p<0.01. In the linear regression analysis, closed circles represent diabetic mice and open circles represent control mice, p<0.01.