Abstract
We examined changes in intraepidermal nerve fibers (IENFs) to differentiate patients
with diabetic neuropathy (DN) and diabetic neuropathic pain (DN-P) from those with
DN without pain (DN-NOP). Punch skin biopsies were collected from the proximal thigh
(PT) and distal leg (DL) of normal subjects, patients with type 2 diabetes without
evidence of DN (DM), or DN-P and DN-NOP patients. Protein gene product 9.5-positive
(PGP+) immunohistochemistry was used to quantify total IENF, and growth-associated
protein 43 (GAP43) for regenerating IENF. Compared to normal subjects and patients
with type 2 diabetes without evidence of DN, both DN-P and DN-NOP have reduced PGP+ IENF
densities in DL and PT. Although GAP43+ IENF densities were also reduced in DL for
both DN-P and DN-NOP, the GAP43+ IENF densities in PT of DN-P remained at the control
levels. Higher GAP43/PGP ratios were detected in DN-P compared to DN-NOP in the DL
and PT. In parallel, increased numbers of axonal swellings per PGP+ fiber (axonal
swelling/PGP) were detected in DN-P compared to normal subjects, patients with type
2 diabetes without evidence of DN, and DN-NOP in the DL. These axonal swellings were
positive for tropomyosin-receptor-kinase A and substance P, suggesting that they are
associated with nociception.
Perspective
Among patients with DN, the ratios of GAP43/PGP and axonal swelling/PGP are likely
to differentiate painful from painless phenotypes.
Key words
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Article info
Publication history
Published online: May 20, 2013
Accepted:
March 11,
2013
Received in revised form:
January 23,
2013
Received:
August 24,
2012
Footnotes
This study is supported by National Institutes of Health (UO1-DK60994 [E.L.F.]; 1K08NS061039 [H.T.C.]; R01DK064814 [A.G.S., J.R.S.]; M01RR0064 [A.G.S., J.R.S.]), the American Diabetes Association (ADA08CR52 [A.G.S., J.R.S.]), and the Juvenile Diabetes Research Foundation Center for the Study of Complications in Diabetes.
This work utilized the Morphology and Image Analysis Core of the Michigan Diabetes Research and Training Center funded by NIH (5P60 DK20572) from the National Institute of Diabetes & Digestive & Kidney Diseases.
The authors have no conflicts of interest, financial or otherwise, related to this study.
Identification
Copyright
© 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.
