Increased peptidergic fibers as a potential cutaneous marker of pain in diabetic small fiber neuropathy

Pall Karlsson, Vincenzo Provitera, Giuseppe Caporaso, Annamaria Stancanelli, Anna Maria Saltalamacchia, Ilaria Borreca, Fiore Manganelli, Lucio Santoro, Troels Staehelin Jensen, Maria Nolano

Research output: Contribution to journalArticlepeer-review


ABSTRACT: Diabetic polyneuropathy (DPN) is a common complication of diabetes and is often associated with neuropathic pain. The mechanisms underlying development and maintenance of painful DPN are largely unknown, and quantification of intraepidermal nerve fiber density from skin biopsy, one of the neuropathological gold standard when diagnosing DPN, does not differentiate between patients with and without pain. Identification of possible pain pathophysiological biomarkers in patients with painful DPN may increase our knowledge of mechanisms behind neuropathic pain. Animal models of painful DPN have been shown to have an increased density of peptidergic nerve fibers (substance P and calcitonin gene-related peptide). In this study, we performed a detailed skin biopsy analysis in a well-characterized group of DPN patients with primarily small fiber involvement, with and without pain, and in healthy controls and test for correlation between skin biopsy findings and pain intensity and quantitative sensory testing. We found that although there was no difference in intraepidermal nerve fiber density using protein gene product 9.5 between patients with and without pain, patients with pain had increased density of dermal peptidergic fibers containing substance P and calcitonin gene-related peptide compared with patients with painless DPN and healthy controls. Peptidergic nerve fiber density correlated with pain ratings in patients with pain (R = 0.33; P = 0.019), but not with quantitative sensory testing results. In this article, we show, for the first time in humans, an increased density of dermal peptidergic fibers in painful DPN. These findings provide new insight in the pathophysiological mechanisms of pain in diabetes and open the research towards new therapeutic targets.

Original languageEnglish
Pages (from-to)778-786
Number of pages9
Issue number3
Publication statusPublished - Mar 1 2021


  • Animals
  • Diabetes Mellitus
  • Diabetic Neuropathies
  • Humans
  • Nerve Fibers
  • Neuralgia
  • Skin
  • Small Fiber Neuropathy/complications


Dive into the research topics of 'Increased peptidergic fibers as a potential cutaneous marker of pain in diabetic small fiber neuropathy'. Together they form a unique fingerprint.

Cite this