Biomedical subjects

Martin Schmelz

Publications and source records attributed to Martin Schmelz.

At least 37 records · Page 2Linked to original sources

PubMed2005

Transcutaneous penetration of toluene in rat skin a microdialysis study.

Percutaneous absorption of lipophilic substances has major implications for therapeutical use or toxicological effects. We, therefore, using dermal microdialysis, measured local toluene concentrations and assessed the effects of duration of exposure, skin barrier disruption and the use of skin-care products. Three microdialysis membranes (3000 kDa) were inserted intradermally at a length of 2 cm in the abdominal skin of 82 anaesthetized male Wistar rats. They were perfused with albumin solution (5%) at 10 microl/min. A skin area of 1.5 x 0.6 cm above the membranes was exposed to toluene (100%, 200 microl) for 15 or 240 min. Dialysate was sampled at 20-min intervals. Using GC-FPD (gas charomotography flame photometric detector), it was analysed for toluene. In addition, the effects of tape stripping and pretreatment with topical products were assessed. In each of the 12 permutations of exposure time, pretreatments and tape stripping, five to eight animals were investigated. Maximum toluene concentrations were reached at 60 min after exposure (3.07 +/- 0.40 microg/ml, 15 min; 5.38 +/- 0.92 microg/ml, 240 min). In 15-min exposure experiments, dermal toluene concentrations decreased slowly to reach baseline values after 240 min. After 240-min exposure, a plateau of approximately 6 microg/ml was reached after 60 min. Neither tape stripping nor the pretreatment with barrier cream induced a significant change on dermal toluene concentrations. The slow kinetics of toluene penetration results in a steep concentration gradient in the skin with very-high local toluene concentrations and a delayed wash out, which might be relevant not only toxicologically, but also therapeutically.

Administration, Cutaneous↗

PubMed2004

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. 25.7 mA, p<0.01) and reached a plateau for intensities above 25 mA, suggesting lower electrical thresholds for sudomotor fibers. Maximum flare areas induced electrically with 30 mA were smaller than those evoked chemically (flare size: 4.5 cm2 vs. 10.6 cm2). In contrast, the electrically evoked sweating rate was higher than that evoked chemically (acetylcholine, or ACh; sweating rate 0.31 vs. 0.21 microl/cm2/min, p<0.01), which might be attributed to an increased effectiveness of synchronized discharge in sympathetic fibers upon electrical stimulation.

Acetylcholine↗

PubMed2004

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, while axon reflex vasodilation was significantly enhanced even on the patients' unaffected limbs (P < 0.05). Our results support the hypothesis that facilitated neurogenic inflammation is a predisposing factor for CRPS. The lack of protein extravasation indicates that an initiating trauma is necessary to induce neuropeptide up-regulation in primary afferents.

Adult↗

PubMed2004

Mechanically induced axon reflex and hyperalgesia in human UV-B burn are reduced by systemic lidocaine.

The mechanisms for the induction of primary mechanical hyperalgesia are unclear. We analyzed the neurogenic axon reflex erythema (flare) following phasic mechanical stimulation in normal and in UV-B irradiated skin. In a cross-over double blind design (n = 10), low dose of systemic lidocaine suppressed mechanical hyperalgesia in sunburned skin and in the mechanically induced flare. Phasic mechanical stimulation, even at painful intensities, did not evoke a flare reaction in normal skin. However, stimulation within the UV-B burn dose-dependently provoked an immediate flare reaction. Systemic lidocaine suppressed the mechanically induced flare as well as the mechanical hyperalgesia in sunburned skin, while leaving the impact-induced ratings in normal skin unchanged. Systemic lidocaine reduced these effects of sensitization, but did not reduce ratings in normal skin. As mechanically insensitive ("sleeping") nociceptors have been shown to mediate the axon-reflex in human skin, sensitization of this class of nociceptors might contribute also to the UV-B-induced primary mechanical hyperalgesia.

Adult↗

PubMed2004

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 liquid chromatography with electrochemical detection. Control experiments were performed in human skin homogenates with and without tyramine incubation. In vivo, norepinephrine (NE) concentration increased from 36.3 +/- 10.2 pg/ml to 84.4 +/- 18.4 pg/ml (P < 0.001) during stimulation with tyramine, dialysate dopamine (DA) concentration increased from 105.2 +/- 36.5 pg/ml to 7162.4 +/- 3972.4 pg/ml (P < 0.001). Both tyramine-induced NE and DA release were dose-dependent (NE: r = 0.438, P < 0.05; DA: r = 0.894, P < 0.001). In skin homogenates, tyramine incubation led to a significant increase of DA concentrations (387.0 +/- 34.8 pg/ml, controls: 13.2 +/- 2.4 pg/ml; P < 0.05), while NE and epinephrine levels remained unchanged. In conclusion, our experiments show that dermal microdialysis is capable of locally measuring catecholamines in human skin. This offers the opportunity to investigate the function of the peripheral sympathetic nervous system. Additional to non-enzymatic oxidation, DA increase probably reflects metabolic degradation of tyramine by non-neuronal pathways and therefore does not reflect local sympathetic innervation.

Adult↗

PubMed2004

The cyclooxygenase isozyme inhibitors parecoxib and paracetamol reduce central hyperalgesia in humans.

Non-steroidal antiinflammatory drugs (NSAIDs) are known to induce analgesia mainly via inhibition of cyclooxygenase (COX). Although the inhibition of COX in the periphery is commonly accepted as the primary mechanism, experimental and clinical data suggest a potential role for spinal COX-inhibition to produce antinociception and reduce hypersensitivity. We used an experimental model of electrically evoked pain and hyperalgesia in human skin to determine the time course of central analgesic and antihyperalgesic effects of intravenous parecoxib and paracetamol (acetaminophen). Fourteen subjects were enrolled in this randomized, double blind, and placebo controlled cross-over study. In three sessions, separated by 2-week wash-out periods, the subjects received intravenous infusions of 40 mg parecoxib, 1000 mg paracetamol, or placebo. The magnitude of pain and areas of pinprick-hyperalgesia and touch evoked allodynia were repeatedly assessed before, and for 150 min after the infusion. While pain ratings were not affected, parecoxib as well as paracetamol significantly reduced the areas of secondary hyperalgesia to pinprick and touch. In conclusion, our results provide clear experimental evidence for the existence of central antihyperalgesia induced by intravenous infusion of two COX inhibitors, parecoxib and paracetamol. Since the electrical current directly stimulated the axons, peripheral effects of the COX inhibitors on nociceptive nerve endings cannot account for the reduction of hyperalgesia. Thus, besides its well-known effects on inflamed peripheral tissues, inhibition of central COX provides an important mechanism of NSAID-mediated antihyperalgesia in humans.

Acetaminophen↗

PubMed2004

Sensitization to bradykinin B1 and B2 receptor activation in UV-B irradiated human skin.

Bradykinin B1 and B2 receptors contribute to nociceptor sensitization under inflammatory conditions. Here, we examined the vascular inflammatory responses and nociceptive effects resulting from activation of B1 and B2 receptors in healthy and UV-B irradiated skin in human volunteers. The B1 receptor agonist des-Arg(10)-Kallidin (10(-6)-10(-3)M) and the B2 receptor agonist bradykinin (10(-9)-10(-4)M) were administered by dermal microdialysis to the ventral thigh. UV-B irradiation was performed 24 h prior to the experiment with the threefold minimum erythemal dose. Pain sensation perceived during the stimulation with the bradykinin receptor agonists was estimated on a numeric scale. Local and axon reflex-induced vasodilations were recorded by laser Doppler imaging. For protein extravasation, total protein content in the dialysate was assessed as a measure of increased endothelial permeability. In normal skin, both B1 and B2 receptor activation dose-dependently evoked pain, vasodilatation and protein extravasation. In UV-B irradiated skin, pain sensation and axon reflex vasodilatation were enhanced by both B1 and B2 agonists, whereas local vasodilatation was increased only following B1 receptor activation. The UV-B irradiation did not enhance B1 and B2 receptor-induced protein extravasation indicating a differential sensitization of the neuronal, but not the vascular response.

Adult↗

PubMed2004

High local concentrations and effects on differentiation implicate interleukin-6 as a paracrine regulator.

OBJECTIVE: To examine the possibility that interleukin-6 (IL-6) can act as a paracrine regulator in adipose tissue by examining effects on adipogenic genes and measuring interstitial IL-6 concentrations in situ. RESEARCH METHODS AND PROCEDURES: Circulating and interstitial IL-6 concentrations in abdominal and femoral adipose tissue were measured using the calibrated microdialysis technique in 20 healthy male subjects. The effects of adipose cell enlargement on gene expression and IL-6 secretion were examined, as well as the effect of IL-6 in vitro on gene expression of adiponectin and other markers of adipocyte differentiation. RESULTS: The IL-6 concentration in the interstitial fluid was approximately 100-fold higher than that in plasma, suggesting that IL-6 may be a paracrine regulator of adipose tissue. This was further supported by the finding that adding IL-6 in vitro at similar concentrations down-regulated the expression of adiponectin, aP2, and PPARgamma-2 in cultured human adipose tissue. In addition, gene expression and release of IL-6, both in vivo and in vitro, correlated with adipose cell size. DISCUSSION: These data suggest that IL-6 may be a paracrine regulator of adipose tissue. Furthermore, increased adipose tissue production of IL-6 after hypertrophic enlargement of the adipose cells may detrimentally affect systemic insulin action by inducing adipose tissue dysfunction with impaired differentiation of the pre-adipocytes and/or adipocytes and lower adiponectin.

Abdomen↗

PubMed2004

Neural activation during experimental allodynia: a functional magnetic resonance imaging study.

Abstract Pain induced by gentle stroking, i.e. dynamic-mechanical allodynia, is one of the most distressing symptoms of neuropathic pain. The underlying neuronal pathways are still a matter of debate. Here, we investigated the cortical activations associated with dynamic-mechanical allodynia in an experimental human pain model by functional magnetic resonance imaging (fMRI). Large and stable areas of brush-evoked allodynia were induced in 11 healthy subjects by topical capsaicin (2.5%, 30 min) application following local heating (45 degrees C for 5 min), thus combining both physical and chemical sensitization. During the fMRI experiments, allodynia was rekindled by local heat application (40 degrees C for 5 min) immediately before the allodynia testing. Brushing the untreated forearm (control condition) led to activations of the contralateral primary somatosensory cortex (S1), contralateral parietal association cortex (PA), bilateral secondary somatosensory cortices (S2) and insula (contralateral). Brushing the allodynic skin was painful and the cortical responses were partially overlapping with those induced by the nonpainful brush stimulation. Additionally, the contralateral inferior frontal cortex (IFC) and the ipsilateral insula were activated. Direct comparison between nonpainful brushing and brush-evoked allodynia revealed significant increases in blood oxygenation level-dependent (BOLD) signals in contralateral S1, PA, IFC and bilateral S2/insula during allodynia. This study highlights the importance of a cortical network comprising S1, PA, S2/insula and IFC in the processing of dynamic-mechanical allodynia in the human brain. Furthermore, it demonstrates that the combined heat/capsaicin model can be used successfully in the exploration of brain processes underlying stimulus-evoked pain.

Adult↗

PubMed2004

Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin.

UNLABELLED: Activation of mast cells and the systemic release of histamine is a common side effect of opioids. Nevertheless, fentanyl and its derivatives show only a slight activation of mast cells with a subsequent liberation of histamine and tryptase. In this study, we used intradermal microdialysis to assess whether this stimulatory effect of opioids on mast cells depends on the activation of opioid receptors. This new approach allowed us to measure the dose-dependent release of histamine and tryptase from mast cells and the subsequent vascular and sensory effect without systemic side effects in volunteers. The opiate codeine and the synthetic opioids meperidine, fentanyl, alfentanil, sufentanil, remifentanil, buprenorphine, and the opioid antagonist naloxone were tested. Only codeine and meperidine induced mast cell activation with the release of tryptase and histamine, leading to protein extravasation, flare reactions, and itch sensations. Because naloxone did not attenuate these effects, it is unlikely that mu-opioid receptors are involved in the activation of mast cells. IMPLICATIONS: Opioid effects on mast cells were assessed using intradermal microdialysis. Mast cell activation was seen with codeine and meperidine; no other opioid induced degranulation. Therefore, histamine release seen at large concentrations of potent micro agonists is caused by an unspecific effect rather than an activation of opioid receptors.

Adult↗

PubMed2004

Perioperative intravenous lidocaine has preventive effects on postoperative pain and morphine consumption after major abdominal surgery.

UNLABELLED: Sodium channel blockers are approved for IV administration in the treatment of neuropathic pain states. Preclinical studies have suggested antihyperalgesic effects on the peripheral and central nervous system. Our objective in this study was to determine the time course of the analgesic and antihyperalgesic mechanisms of perioperative lidocaine administration. Forty patients undergoing major abdominal surgery participated in this randomized and double-blinded study. Twenty patients received lidocaine 2% (bolus injection of 1.5 mg/kg in 10 min followed by an IV infusion of 1.5 mg. kg(-1). h(-1)), and 20 patients received saline placebo. The infusion started 30 min before skin incision and was stopped 1 h after the end of surgery. Lidocaine blood concentrations were measured. Postoperative pain ratings (numeric rating scale of 0-10) and morphine consumption (patient-controlled analgesia) were assessed up to 72 h after surgery. Mean lidocaine levels during surgery were 1.9 +/- 0.7 microg/mL. Patient-controlled analgesia with morphine produced good postoperative analgesia (numeric rating scale at rest, <or=3; 90%-95%; no group differences). Patients who received lidocaine reported less pain during movement and needed less morphine during the first 72 h after surgery (103.1 +/- 72.0 mg versus 159.0 +/- 73.3 mg; Student's t-test; P < 0.05). Because this opioid-sparing effect was most pronounced on the third postoperative day, IV lidocaine may have a true preventive analgesic activity, most likely by preventing the induction of central hyperalgesia in a clinically relevant manner. IMPLICATIONS: The perioperative administration of systemic small-dose lidocaine reduces pain during surgery associated with the development of pronounced central hyperalgesia, presumably by affecting mechanoinsensitive nociceptors, because these have been linked to the induction of central sensitization and were shown to be particularly sensitive to small-dose lidocaine.

Abdomen↗

PubMed2004

The effect of intravenous infusion of adenosine on electrically evoked hyperalgesia in a healthy volunteer model of central sensitization.

Human pain models invoking central sensitization, one of the key mechanisms of chronic pain, may be useful for characterizing new analgesics. A new model of electrical hyperalgesia can detect the efficacy of several analgesic mechanisms. Because IV adenosine can alleviate neuropathic pain, we investigated its effect on experimental sensitization. This was a double-blinded, randomized, two-period crossover study in 20 healthy volunteers. Current pulses (0.5 ms; 1 Hz) were applied intracutaneously to achieve pain rating of approximately 5 on a 0-10 numeric rating scale. Pain, areas of pinprick hyperalgesia, and tactile allodynia were assessed during the 2.5-h stimulation period. Adenosine (50 microg. kg(-1). min(-1)) and placebo were infused IV over 60 min. Additional testing was performed 24 h after each treatment. Adenosine reduced the area of pinprick hyperalgesia during the infusion compared with placebo; there was no significant effect on tactile allodynia or pain rating. The effect on hyperalgesia developed over 15 min and was significant (P < or = 0.05) for the rest of the infusion period. There was no difference between treatments at 24 h. Thus, in accordance with reports on neuropathic pain, adenosine reduced central sensitization in the human model of electrical hyperalgesia. However, adenosine did not have the long-term effects seen in patients. The model can investigate mechanisms of drugs for the treatment of chronic pain.

Adenosine↗

PubMed2004

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 feet (P < 0.001) and thighs (P < 0.007). Furthermore, electrical thresholds for flare induction were increased (thighs P < 0.001 and feet P < 0.03). In NO-Ns, flare size at the feet (P < 0.02) and flux at both sites (thighs P < 0.001 and feet P < 0.002) were even increased. Test/retest evaluation of our method revealed a good correlation (r = 0.83, P < 0.004). Intracutaneous electrical stimulation of C-fibers and scanning the flare with LDI is a sensitive tool to reliably detect small fiber impairment in diabetic SFN subjects and even increased neuropeptide release in NO-Ns.

Adult↗

PubMed2003

No alpha-adrenoreceptor-induced C-fiber activation in healthy human skin.

In healthy volunteers, flare responses induced by norepinephrine (NE) iontophoresis have been observed. However, as NE iontophoresis is a combined electrical and chemical stimulus axon, reflexes cannot be directly linked to pharmocological activity of NE. Different concentrations of NE, clonidine (CL), and phenylephrine (PE) (NE: 10(-10)-10(-3) M; CL and PE: 10(-8)-10(-3) M) were applied via intradermal microdialysis fibers into the skin of healthy volunteers. Simultaneously, skin blood flow was visualized by laser-Doppler imaging scans and quantified in a vasoconstriction skin area directly above the membranes to control drug effects and in expected axon reflex vasodilation areas that were 0.75 cm apart. NE, PE, and CL caused dose-dependent vasoconstriction. However, neither in the presumed axon reflex areas (quantitative analysis) nor on laser-Doppler imaging pictures (qualitative analysis) were any vasodilation observed. Even at concentrations causing maximum vasoconstriction (10(-3) M for any drug), no vasodilation was induced. Our results indicate that, in healthy human skin, exogenously supplied alpha-adrenoreceptor agonists alone do not activate nociceptors sufficiently to induce axon reflex flare.

Adrenergic alpha-Agonists↗

PubMed2003

Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin.

We examined whether neuronal proteinase-activated receptor-2 (PAR-2) may be involved in pruritus of human skin. The endogenous PAR-2 agonist tryptase was increased up to fourfold in atopic dermatitis (AD) patients. PAR-2 was markedly enhanced on primary afferent nerve fibers in skin biopsies of AD patients. Intracutaneous injection of endogenous PAR-2 agonists provoked enhanced and prolonged itch when applied intralesionally. Moreover, itch upon mast cell degranulation was abolished by local antihistamines in controls but prevailed in AD patients. Thus, we identified enhanced PAR-2 signaling as a new link between inflammatory and sensory phenomena in AD patients. PAR-2 therefore represents a promising therapeutic target for the treatment of cutaneous neurogenic inflammation and pruritus.

Adult↗

PubMed2003

Itch.

Itch is a common skin sensation, with substantial effects on behaviour. Neurophysiological research has permitted accurate definition of neural pathways of itch, and has confirmed the distinctiveness of itch pathways in comparison with pain. A clinical classification of itch, based on such improved understanding, describes the difference between peripheral (pruritoceptive) and central (neurogenic or neuropathic) itch. New specific and sensitive investigational methods in people and animals enable us to better understand this bothersome symptom, and have important clinical implications. We describe the clinical classification of itch, new findings on neuropathophysiology of itch, methods for assessment, and improved treatments.

Animals↗

PubMed2003

Neuronal sensitization for histamine-induced itch in lesional skin of patients with atopic dermatitis.

OBJECTIVE: Lowered threshold of neurons (ie, neuronal sensitization) in atopic dermatitis was investigated by testing sensitivity to histamine. DESIGN: Comparative study. SETTING: A dermatological clinic and a research laboratory. PARTICIPANTS: Eighteen patients with atopic dermatitis (AD) and 6 patients with chronic plaque-type psoriasis as well as 14 healthy control subjects. INTERVENTIONS: Histamine prick was performed in lesional and nonlesional skin of patients and in control subjects. MAIN OUTCOME MEASURES: Axon reflex flare and wheal were measured planimetrically, and the itch intensity was rated on a numerical scale (0-10). RESULTS: In nonlesional skin of patients with AD, itch intensity and axon reflex flare were both significantly smaller compared with controls (mean +/- SEM maximum itch, 1.5 +/- 0.3 vs 3.1 +/- 0.2 [P<.05]; mean +/- SEM diameter, 12.3 +/- 2.0 vs 25.3 +/- 2.5 mm [P<.01]). In lesional skin of patients with AD, on the contrary, massive itch was provoked (maximum itch, 4.4 +/- 0.3), although flare was relatively small (diameter, 16.1 +/- 3.4 mm). Itch ratings in patients with psoriasis were low both in lesional and nonlesional skin (maximum itch, 1.3 +/- 0.6 and 1.0 +/- 0.4, respectively). CONCLUSION: As the area of axon reflex flare is an indirect measure of activity in primary afferent neurons, our results suggest a decreased activation of peripheral pruriceptors in patients with AD. The massively increased itch in lesional skin of patients with AD might therefore be based on sensitization for itch in the spinal cord rather than in primary afferent neurons. This sensitization does not appear to be simply based on skin inflammation because histamine-induced itch was not augmented in lesional skin of psoriasis.

Adult↗

PubMed2003

Neurophysiology of pruritus: cutaneous elicitation of itch.

Itching is defined as an unpleasant cutaneous sensation leading to the desire to scratch. It serves as a physiological self-protective mechanism as do other cutaneous sensations like pain, touch, vibration, cold, and heat to help defend the skin against harmful external agents. Pruritus can be evoked in the skin directly by mechanical and thermal stimuli or indirectly through chemical mediators. It may also be generated in the central nervous system independently of peripheral stimulation. Single-nerve-fiber recordings have shown that histamine-evoked itch is transmitted by selective slow-conducting subpopulations of unmyelinated C-polymodal neurons. Recent experimental studies using improved methods have demonstrated which of the suspected chemical itch mediators such as histamine, neuropeptides, prostaglandins, serotonin, acetylcholine, or bradykinin act pruritogenically on C-fibers. Moreover, investigations have revealed new receptor systems such as vanilloid, opioid, and cannabinoid receptors on cutaneous sensory nerve fibers that may modulate itch and thereby represent targets for antipruritic therapy. This review focuses on the peripheral generation of itch, including neurotransmitters, neuropeptides, and inflammatory mediators.

Humans↗