Increased Axonal Regeneration and Swellings in Intraepidermal Nerve Fibers Characterize Painful Phenotypes of Diabetic Neuropathy

• Published in: The journal of pain Vol. 14; no. 9; pp. 941 - 947
• Main Authors: Cheng, Hsinlin T, Dauch, Jacqueline R, Porzio, Michael T, Yanik, Brandon M, Hsieh, Wilson, Smith, A.Gordon, Singleton, J.Robinson, Feldman, Eva L
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2013
• Subjects: Aged; Anesthesia & Perioperative Care; Axons - pathology; Diabetic Neuropathies - complications; Diabetic pain; Epidermis - innervation; Female; GAP-43 Protein - metabolism; Humans; intraepidermal nerve fiber; Male; Middle Aged; Nerve Degeneration; Nerve Fibers - metabolism; Nerve Fibers - pathology; Neuralgia - etiology; Pain Measurement; Pain Medicine; peripheral neuropathy; Receptor, trkA - metabolism; Substance P - metabolism; TRPV Cation Channels - metabolism; peripheral neuropathy; intraepidermal nerve fiber; Diabetic pain
• ISSN: 1526-5900; 1528-8447; 1528-8447
• DOI: 10.1016/j.jpain.2013.03.005

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.