Catecholamine release in human skin--a microdialysis study.

Dermal microdialysis might be a promising tool to investigate properties of sympathetic neurons in the skin as investigation of peripheral noradrenergic neurons in humans usually relies on highly variable vasoconstrictor reflexes or on indirect measurements like skin temperature recordings. To evaluate this technique, 21 experiments were performed in 15 healthy subjects with four intracutaneous microdialysis fibers (diameter, 200 microm; cutoff, 5 kDa) at hands or feet. After 60 min, saline perfusion tyramine at concentrations of 0.195 to 200 microg/ml was applied for 15 min followed by a 15-min saline perfusion again. Catecholamine concentrations were detected through high-performance liqu…

Botulinum Toxin A reduces neurogenic flare but has almost no effect on pain and hyperalgesia in human skin.

Botulinum toxin A (BoNT/A) has been used therapeutically to treat muscular hypercontractions and sudomotor hyperactivity. There is increasing evidence that BoNT/A might also have analgesic properties, in particular in headache. In the present investigation we tested the often cited hypothesis that BoNT/A-induced analgesia can be attributed to inhibition of neuropeptide release from nociceptive nerve fibers. In 15 healthy volunteers BoNT/A (5, 10, 20 mouse units BOTOX) or saline (contralateral side) was injected intracutaneously on the volar forearm. On day zero, the day of injection, no further tests were performed. We repeatedly elicited pain, mechanical hyperalgesia and neurogenic flare b…

Electrically stimulated axon reflexes are diminished in diabetic small fiber neuropathies.

Axon reflex mediated flare depends on the density and the function of cutaneous C-fibers and may be impaired in diabetic neuropathy. We induced neurogenic axon reflex flare by intracutaneous electrical stimulation and analyzed size and intensity of the flare on the dorsum of the foot and ventral thigh with laser Doppler imaging (LDI). We investigated 12 diabetic subjects with small fiber neuropathies (SFNs), 5 diabetic subjects without neuropathy (NO-Ns), and 14 healthy control subjects. Five of the normal subjects were reassessed after 12 months. In comparing patients with SFN to control subjects, we found that SFN flare size but not the intensity of vasodilation (flux) was reduced on the …

Thoracoscopic sympathectomy at the T2 or T3 level facilitates bradykinin-induced protein extravasation in human forearm skin.

Background.  The endogenous peptide bradykinin (BK) is an inflammatory mediator that induces nociceptor activation and sensitization as well as protein extravasation and vasodilation. Objective.  To test the hypothesis if sympathectomy affects BK-induced inflammation in humans. Methods.  Dermal microdialysis was employed on the volar forearm in 10 patients (21–41 years) with regional hyperhidrosis before and three months after preganglionic endoscopic transthoracic sympathetic clipping (ETSC) at the T2 or T3 level and in 10 healthy volunteers (22–36 years). After 60 minutes perfusion with Ringer's solution microdialysis fibers were perfused with BK 10−7 M and 10−5 M for 30 minutes followed …

Inhibition of neutral endopeptidase (NEP) facilitates neurogenic inflammation

Neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) are involved in neuropeptide degradation and may modulate neurogenic inflammation. We therefore explored the effect of specific blockers of NEP and ACE on the intensity of neurogenic inflammation. We investigated eight subjects on three occasions. Two pairs of microdialysis fibers equipped with intraluminal wires were inserted intracutaneously into the volar forearms and electrical stimuli were delivered via the intraluminal electrodes. The microdialysis fibers were perfused either with normal saline, phosphoramidon (NEP inhibitor), or captopril (ACE inhibitor). CGRP release was assessed in the microdialysis eluate via a sp…

Chemically and electrically induced sweating and flare reaction

Both thin afferent (nociceptors) and efferent (sympathetic sudomotor) nerve fibers can be activated electrically and chemically, resulting in neurogenic erythema and sweating. These reactions have been used before to assess the impairment of sympathetic and nociceptor fibers in humans. In this study, electrically induced sweating and erythema were assessed simultaneously in the foot dorsum and thigh, and were compared to chemically induced activation. Reproducible intensity-response relations (stimulation intensities 0-30 mA, 1 Hz) were obtained from 32 subjects. The steepest increase of the sweat response was induced at lower intensities as compared to that of the erythema (18.3 mA vs. 25.…

Influence of vagus nerve stimulation on histamine-induced itching

To investigate whether vagus nerve stimulation (VNS) reduces pruritus in humans.Recently, it has been shown that VNS has antinociceptive and antidepressant effects in humans.Eleven patients were investigated before (baseline) and during chronic VNS treatment. The experiments were performed at two different stimulation intensities: 2 to 5 days after implantation at a low stimulation intensity (mean intensity 0.7 +/- 0.2 mA, second session) and after 8 to 14 weeks of VNS therapy (mean intensity 1.4 +/- 0.3 mA, third session). Twelve healthy age- and sex-matched subjects were investigated using the same experimental protocol. Itch was induced by histamine-iontophoresis and quantified on a visu…

Facilitated neurogenic inflammation in unaffected limbs of patients with complex regional pain syndrome.

Pain, edema, increased skin temperature, reddening and trophic changes characterize complex regional pain syndrome (CRPS). Recently, we have been able to show facilitated neurogenic inflammation on the affected limb. In the current study unaffected limbs were examined after resolution of the CRPS symptoms to assess possible generalized changes predisposing to CRPS. In 12 patients and in 12 healthy volunteers dermal microdialysis in combination with electrical C-fiber stimulation was employed to induce neuropeptide release. Dialysate protein concentration and axon reflex vasodilation were measured. Neither in patients nor in controls did electrical stimulation lead to protein extravasation, …

Substance-P-induced protein extravasation is bilaterally increased in complex regional pain syndrome.

Pain, mechanical hyperalgesia, edema, increased skin temperature, and skin reddening are characteristic symptoms of acute complex regional pain syndrome (CRPS). We have recently demonstrated facilitated neurogenic inflammation on the affected limb. To further elucidate the underlying mechanisms, exogenous substance P (SP) in ascending concentrations (10(-9), 10(-8), 10(-7), 10(-6) M) was intradermally applied to the affected and the unaffected limbs, respectively, in two groups of 11 CRPS patients each using the microdialysis technique. Fourteen healthy volunteers served as controls for SP application, and 9 volunteers and 10 patients served as controls for saline perfusion. Dialysate prote…

A polymorphic locus in the intron 16 of the human angiotensin-converting enzyme (ACE) gene is not correlated with complex regional pain syndrome I (CRPS I).

Exaggerated neurogenic inflammation has been recognized to be one reason for many CRPS symptoms. Since angiotensin-converting enzyme (ACE) is a key enzyme for the termination of neurogenic inflammation, it has been selected as a candidate gene for CRPS predisposition. A previous report of an insertion/deletion (I/D) polymorphism in intron 16 within the ACE gene implicated an increased risk to develop CRPS I associated with the D allele. However, in the present study the D allele frequency was not increased in CRPS I cases (0.51 for D allele, 0.49 for I allele). Furthermore, there was no co-segregation of any genotype (DD, ID, II) with the CRPS phenotype in 12 selected familial CRPS I cases …

Corrigendum to “Inhibition of neutral endopeptidase (NEP) facilitates neurogenic inflammation” [Exp. Neurol. 195 (2005) 179–184]

Angiotensin converting enzyme has an inhibitory role in CGRP metabolism in human skin

The neutral endopeptidase (NEP) is important for calcitonin gene related peptide (CGRP) degradation, while the role of angiotensin converting enzyme (ACE) remains unclear. By using dermal microdialysis we explored the effect of phosphoramidon (NEP blocker), captopril (ACE blocker) and a mixture of both drugs on the intensity of electrically-induced CGRP-mediated neurogenic flare. The results reveal that phosphoramidon elevated flare intensity, but that this was not further increased by adding captopril. In contrast, neurogenic flare was decreased when the drug mixture was applied in compared to NEP only. Electrically released CGRP levels could be measured directly in perfusates containing p…

Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS)

This review explains symptoms and nature of neuropeptide signaling and its importance for clinical symptoms of CRPS. Neurogenic inflammation regularly accompanies excitation of primary afferent nociceptors. It has two major components-plasma extravasation and vasodilatation. The most important mediators are the calcitonin gene-related peptide (CGRP) and substance P (SP). After peripheral trauma immune reaction (e.g. cytokines) and the attempts of the tissue to regenerate (e.g. growth factors) sensitize nociceptors and amplify neurogenic inflammation. This cascade of events has been demonstrated in rat models of CRPS. Clinical findings in these animals strongly resemble clinical findings in …

Skin innervation at different depths correlates with small fibre function but not with pain in neuropathic pain patients

Background: Neuropathy can lead not only to impaired function but also to sensory sensitization. We aimed to link reduced skin nerve fibre density in different levels to layer-specific functional impairment in neuropathic pain patients and tried to identify pain-specific functional and structural markers. Methods: In 12 healthy controls and 36 patients with neuropathic pain, we assessed clinical characteristics, thermal thresholds (quantitative sensory testing) and electrically induced pain and axon reflex erythema. At the most painful sites and at intra-individual control sites, skin biopsies were taken and innervation densities in the different skin layers were assessed. Moreover, neurona…