• Malik Bechakra, Mariska D Nieuwenhoff, Rosmalen Joost van JV Dept. of Biostatistics, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands., Groeneveld Geert Jan GJ Centre for Human Drug Research, Zernikedreef 8, 2333CL Leiden, the Netherlands., J P M Huygen Frank F Dept. of Anesthesiology, Erasmus MC, Dr. Molewaterplein 40, 3015GD Rotterdam, the Netherlands., Zeeuw Chris I de CI Dept. of Neuroscience, Erasmus MC, Dr. Molewaterplein 50, 3015GE Rotterdam, the Netherlands; Netherlands Institute for Neuroscience, Royal Academy of , Doorn Pieter A van PAV Dept. of Neurology, Erasmus MC, Dr. Molewaterplein 40, 3015GD Rotterdam, the Netherlands., and Jongen Joost L M JLM Dept. of Neurology, Erasmus MC, Dr. Molewaterplein 40, 3015GD Rotterdam, the Netherlands. Electronic address: j.jongen@erasmusmc.nl..
• Dept. of Neurology, Erasmus MC, Dr. Molewaterplein 40, 3015GD Rotterdam, the Netherlands; Dept. of Neuroscience, Erasmus MC, Dr. Molewaterplein 50, 3015GE Rotterdam, the Netherlands.
• Brain Res. 2020 Mar 1; 1730: 146621.

AbstractConsistent associations between the severity of neuropathic pain and cutaneous innervation have not been described. We collected demographic and clinical data, McGill Pain Questionnaires (MPQ) and skin biopsies processed for PGP9.5 and CGRP immunohistochemistry from patients with bortezomib-induced peripheral neuropathy (BiPN; n = 22), painful diabetic neuropathy (PDN; n = 16), chronic idiopathic axonal polyneuropathy (CIAP; n = 16) and 17 age-matched healthy volunteers. Duration of neuropathic symptoms was significantly shorter in patients with BiPN in comparison with PDN and CIAP patients. BiPN was characterized by a significant increase in epidermal axonal swellings and upper dermis nerve fiber densities (UDNFD) and a decrease in subepidermal nerve fiber densities (SENFD) of PGP9.5-positive fibers and of PGP9.5 containing structures that did not show CGRP labeling, presumably non-peptidergic fibers. In PDN and CIAP patients, intraepidermal nerve fiber densities (IENFD) and SENFD of PGP9.5-positive and of non-peptidergic fibers were decreased in comparison with healthy volunteers. Significant unadjusted associations between IENFD and SENFD of CGRP-positive, i.e. peptidergic, fibers and the MPQ sensory-discriminative, as well as between UDNFD of PGP9.5-positive fibers and the MPQ evaluative/affective component of neuropathic pain, were found in BiPN and CIAP patients. No significant associations were found in PDN patients. Cutaneous innervation changes in BiPN confirm characteristic features of early, whereas those in CIAP and PDN are in line with late forms of neuropathic pathology. Our results allude to a distinct role for non-peptidergic nociceptors in BiPN and CIAP patients. The lack of significant associations in PDN may be caused by mixed ischemic and purely neuropathic pain pathology.Copyright © 2020 Elsevier B.V. All rights reserved.

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