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

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  • Pall Karlsson
  • Vincenzo Provitera, Istituti Clinici Scientifici Maugeri IRCCS
  • ,
  • Giuseppe Caporaso, Istituti Clinici Scientifici Maugeri IRCCS
  • ,
  • Annamaria Stancanelli, Istituti Clinici Scientifici Maugeri IRCCS
  • ,
  • Anna Maria Saltalamacchia, Istituti Clinici Scientifici Maugeri IRCCS
  • ,
  • Ilaria Borreca, Istituti Clinici Scientifici Maugeri IRCCS
  • ,
  • Fiore Manganelli, Univ Naples Federico II, University of Naples Federico II, Dept Neurosci Reprod & Odontostomatol Sci
  • ,
  • Lucio Santoro, Univ Naples Federico II, University of Naples Federico II, Dept Neurosci Reprod & Odontostomatol Sci
  • ,
  • Troels Staehelin Jensen
  • Maria Nolano, Univ Naples Federico II, University of Naples Federico II, Dept Neurosci Reprod & Odontostomatol Sci, Istituti Clinici Scientifici Maugeri IRCCS

Diabetic polyneuropathy (DPN) is a common complication to 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 (IENFD) 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 (SP) and Calcitonin-gene related peptide (CGRP)). 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 (QST). We found that while there was no difference in IENFD using PGP 9.5 between patients with and without pain, patients with pain had increased density of dermal peptidergic fibers containing SP and CGRP compared to 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 QST results. Here 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 opens the research towards new therapeutic targets.

Original languageEnglish
JournalPain
Volume162
Issue3
Pages (from-to)778-786
Number of pages9
ISSN0304-3959
DOIs
Publication statusPublished - Mar 2021

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