Electrically evoked neuropeptide release and neurogenic inflammation differ between rat and human skin

Abstract

Protein extravasation and vasodilatation can be induced by neuropeptides released from nociceptive afferents (neurogenic inflammation). We measured electrically evoked neuropeptide release and concomitant protein extravasation in human and rat skin using intradermal microdialysis. Plasmapheresis capillaries were inserted intradermally at a length of 1.5 cm in the volar forearm of human subjects or abdominal skin of rats. Capillaries were perfused with Ringer solution at a flow rate of 2.5 or 1.6 μl min−1. After a baseline period of 60 min capillaries were stimulated electrically (1 Hz, 80 mA, 0.5 ms or 4 Hz, 30 mA, 0.5 ms) for 30 min using a surface electrode directly above the capillaries and a stainless‐steel wire inserted in the capillaries. Total protein concentration was assessed photometrically and calcitonin gene‐related peptide (CGRP) and substance P (SP) concentrations were measured by enzyme‐linked immunosorbent assay (ELISA). In rat skin, electrical stimulation increased CGRP and total protein concentration in the dialysate. SP measurements showed a larger variance but only for the 1 Hz stimulation was the increased release significant. In human skin, electrical stimulation provoked a large flare reaction and at a frequency of 4 Hz both CGRP and SP concentrations increased significantly. In spite of the large flare reactions no protein extravasation was induced, which suggests major species differences. It will be of interest to investigate whether the lack of neurogenic protein extravasation is also valid under pathophysiological conditions.

Electrically Stimulated Axon Reflexes Are Diminished in Diabetic Small Fiber Neuropathies

“…In previous studies, this setting and the frequency of 1 Hz has proven to be most effective in provoking axon reflex vasodilation in human skin (17). This technique guarantees the induction of a flare being constant for even more than 1 h (20).…”

“…In contrast, previous experiments have shown that neurogenic flare in human skin can be reliably induced with low variation by electrical current (17). In this study we employed standardized electrical stimulation at a high current density.…”

The action of CGRP and SP on cultured skin fibroblasts

“…Sympathetically dependent neurogenic inflammation triggers a strong arteriolar vasodilation effect that modulates the amount of inflammatory mediators (such as histamine, arachidonic acid, bradykinin, and prostaglandins, typical of the inflammatory phase that will follow) and the global recruitment of immune-inflammatory cells, which together activate the inflammatory phase of wound healing [1,2,43,44]. As a direct consequence, the neurogenic inflammation promotes the release of cytokines and growth factors, inducing extracellular matrix synthesis by fibroblasts in the healing phase.…”

Inflammatory consequences of cutaneous stimulation

“…In humans, the axon-reflex flare is mediated primarily by calcitonin gene-related peptide (CGRP) with an additional contribution from substance P (Sauerstein et al, 2000).…”

“…Thus, the net result following nociceptor activation might depend on the relative concentrations of proinflammatory neuropeptides, such as substance P, and anti-inflammatory neuropeptides like CGRP. In human skin, a predominance of CGRP secreted from the peripheral terminals of nociceptive neurons during axon-reflex flares (Sauerstein et al, 2000) may explain why TNF-α did not increase following intradermal electrical stimulation in the study by Eberle et al (2010). It would be interesting to determine whether electrical stimulation is more effective in inflammatory and neuropathic pain syndromes characterized by heightened TNF-α signaling, because confirmation of a vicious circle between substance P and cytokine release could lead to insights about the pathogenesis of these syndromes.…”