Sensitized vasoactive C-nociceptors: key fibers in peripheral neuropathic pain

Julia Forstenpointner, Dennis Naleschinski, Gunnar Wasner, Philipp Hüllemann, Andreas Binder, Ralf Baron, Julia Forstenpointner, Dennis Naleschinski, Gunnar Wasner, Philipp Hüllemann, Andreas Binder, Ralf Baron

Abstract

Introduction: Multiple mechanisms are involved in the development and persistence of neuropathic pain. Some patients with nerve damage will remain painless and develop a "loss of function" phenotype, whereas others develop painful neuropathies.

Objectives: The aim of this study is to investigate the role of a peripheral nervous system sensitization by analyzing patients with and without pain.

Methods: The topical application of capsaicin was investigated in peripheral nociceptors. Two groups of patients (painful vs painless) with length-dependent neuropathies and small-fiber impairment were tested. Quantitative sensory testing was assessed before and after topical application of 0.6% capsaicin in the affected skin. In addition, blood perfusion measurements and an axon reflex flare assessment were performed.

Results: Quantitative testing revealed that heat hyperalgesia was induced in all patients and volunteers (P < 0.01) without observing any significant differences between patient groups. By contrast, the extent of the axon reflex flare reaction (P < 0.01) as well as the blood perfusion (P < 0.05) was significantly greater in patients with pain than in neuropathy patients not experiencing pain.

Conclusion: Hyperexcitable vasoactive nociceptive C fibers might contribute to pain in peripheral neuropathies and therefore may serve as a key player in separating into a painless or painful condition.

Keywords: Heat pain threshold; Peripheral neuropathy; Quantitative sensory testing; Vasoactive c-nociceptors.

Conflict of interest statement

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Figures

Figure 1.
Figure 1.
QST profiles. Indicated are QST profiles of the painful (1), painless (2) and healthy control group (3), before and after capsaicin (CAP) application. Each QST parameter is displayed as boxplot (minimum, maximum, median, and first and third quartiles). Intraindividual statistical testing (ie, before vs after capsaicin application) was conducted using the Wilcoxon signed–rank test. Interindividual statistical testing (ie, between patient groups and healthy cohort) was conducted using the Mann–Whitney U test. ***<0.001, **<0.01, n.s. >0.05. CPT, cold pain threshold; HPT, heat pain threshold; QST, quantitative sensory testing.
Figure 2.
Figure 2.
Capsaicin challenge and vasoactive reaction. (A) Setup of the experimental capsaicin application procedure. In the application area, the capsaicin patch was applied and the sensory testing was conducted. In the primary area, the continuous blood perfusion measurement as well as the margin of the axon reflex erythema was determined. (B) The axon reflex flare area (cm2) after 15 minutes of topical capsaicin application is displayed as boxplot (minimum, maximum, median, and first and third quartiles). There were no significant differences between the patient groups and healthy subjects. Capsaicin induced a larger axon reflex flare in the neuropathic pain patients than in the patients without pain. The application area (9 cm2) was not included in the total axon reflex flare size. Interindividual statistical testing for axon reflex flare area was conducted using the Mann–Whitney U test. **<0.01. (C) Displayed is the time course of mean (±SEM) blood perfusion change (arbitrary perfusion units, % change [PU%]) in the primary area and the mean (±SEM) pain rating change (numeric rating scale 0–10) during capsaicin challenge. Interindividual statistical testing for maximum pain ratings (ie, at minute 15) was conducted using the Mann–Whitney U test (statistically not significant). (D) The area under the curve for blood perfusion (AUC [PU%]) is displayed as boxplot. Indicated is a significant difference between the patients with pain as compared to the painless and normal subgroups. Interindividual statistical testing for mean blood perfusion (AUC) between subgroups was conducted using the Mann–Whitney U test. *<0.05.

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