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

doi:10.1097/j.pain.0000000000002054

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

Department of Clinical Medicine - The Danish Pain Research Center
Department of Clinical Medicine - Core Centre for Molecular Morphology, Section for Stereology and Microscopy

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

31 Citations (Scopus)

Abstract

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 language	English
Journal	Pain
Volume	162
Issue	3
Pages (from-to)	778-786
Number of pages	9
ISSN	0304-3959
DOIs	https://doi.org/10.1097/j.pain.0000000000002054
Publication status	Published - 1 Mar 2021

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10.1097/j.pain.0000000000002054

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title = "Increased peptidergic fibers as a potential cutaneous marker of pain in diabetic small fiber neuropathy",

abstract = "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.",

author = "Pall Karlsson and Vincenzo Provitera and Giuseppe Caporaso and Annamaria Stancanelli and Saltalamacchia, {Anna Maria} and Ilaria Borreca and Fiore Manganelli and Lucio Santoro and Jensen, {Troels Staehelin} and Maria Nolano",

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Increased peptidergic fibers as a potential cutaneous marker of pain in diabetic small fiber neuropathy. / Karlsson, Pall; Provitera, Vincenzo; Caporaso, Giuseppe et al.
In: Pain, Vol. 162, No. 3, 01.03.2021, p. 778-786.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Increased peptidergic fibers as a potential cutaneous marker of pain in diabetic small fiber neuropathy

AU - Karlsson, Pall

AU - Provitera, Vincenzo

AU - Caporaso, Giuseppe

AU - Stancanelli, Annamaria

AU - Saltalamacchia, Anna Maria

AU - Borreca, Ilaria

AU - Manganelli, Fiore

AU - Santoro, Lucio

AU - Jensen, Troels Staehelin

AU - Nolano, Maria

PY - 2021/3/1

Y1 - 2021/3/1

N2 - 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.

AB - 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.

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U2 - 10.1097/j.pain.0000000000002054

DO - 10.1097/j.pain.0000000000002054

M3 - Journal article

C2 - 32833793

SN - 0304-3959

VL - 162

SP - 778

EP - 786

JO - Pain

JF - Pain

IS - 3

ER -

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

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