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Biomedical subjects

H O Handwerker

Publications and source records attributed to H O Handwerker.

At least 73 records · Page 4Linked to original sources
PubMed1994

Different patterns of hyperalgesia induced by experimental inflammation in human skin.

Different types of hyperalgesia were studied after experimental induction of inflammation in small skin areas of healthy volunteers either by topical application of capsaicin solution (1% in 70% ethanol) or by briefly freezing a skin area of similar size to -28 degrees C. Sensory tests were performed 30 min after capsaicin application and 22 h after freeze lesions. Heat pain thresholds were lowered after both treatments, probably due to nociceptor sensitization. Hyperalgesia to four types of mechanical stimulation was studied. (i) Hyperalgesia to punctate stimuli was encountered at the skin site directly affected by the noxious chemical or freeze stimulus (1 degree zone) and in the surrounding skin (2 degrees zone) in both models though the area of 2 degrees hyperalgesia to punctate stimuli after freezing was smaller than after capsaicin. (ii) Hyperalgesia to gently brushing the skin was prominent after capsaicin in 1 degree and 2 degrees zone, but almost absent after freezing. It was concluded that both hyperalgesia to punctate stimuli and brush-evoked pain are due to central nervous plasticity changes rather than nociceptor sensitization. As revealed by differential nerve blocks, brush-evoked pain is mediated by low threshold mechanosensitive A beta-fibres, whilst hyperalgesia to punctate stimuli can be elicited when only C-fibres conduct. In contrast to hyperalgesia to punctate stimuli it requires continuous background discharges in nociceptor units. (iii) Pressure hyperalgesia to tonic stimulation with a blunt probe was encountered in the 1 degree zone of both types of inflammation and is probably due to recruitment of sensitized nociceptor units. (iv) Impact hyperalgesia was studied by shooting small bullets against the skin at predetermined velocities. It was found in the 1 degree zone after freezing and absent in the capsaicin model. Differential nerve blocks revealed that it is probably mediated by sensitized C-fibres. In conclusion, different types of inflammatory changes may result in characteristic different patterns of hyperalgesia.

Adult↗
PubMed1994

Differential ability of human cutaneous nociceptors to signal mechanical pain and to produce vasodilatation.

We investigated the ability of human nociceptive primary afferent neurons to encode mechanical pain and to produce vasodilatation. Pain was induced by shooting a light metal cylinder (0.3 g) at different velocities (6-18 m/sec) perpendicularly against the hairy skin of the hand. When single impact stimuli were applied, monotonically increasing stimulus-response functions were obtained in 10 psychophysical experiments using magnitude estimation techniques. In 35 microneurographic experiments nine unmyelinated afferents were recorded from the superficial radial nerve. All units responded readily to impact stimulation even at stimulus intensities that were not rated as painful. However, there was a close linear correlation between the number of action potentials evoked from the nociceptors and the psychophysical magnitude estimates of the perceived sensation or the stimulus intensity. This was also reflected by a corresponding increase of neurogenic vasodilatation. While two thin myelinated afferents displayed qualitatively similar responses 12 low-threshold mechanosensitive afferents (4 rapidly adapting, 5 slowly adapting type 1, 3 slowly adapting type II) failed to encode the intensity of the applied impact force and often became desensitized. This indicates that the total number of action potentials is the determinant of the magnitude of mechanical pain and the associated vasodilatation following single brief stimuli. By contrast, the close correlation between nociceptor activity and sensation changed when trains of mechanical impact stimuli (five stimuli of constant intensity, intratrain frequency of 1/32 to 2 Hz) were applied. Magnitude estimates of pain intensity were frequency dependent and stimuli with short interstimulus intervals were perceived as more painful than those delivered with long intervals. However, the total number of action potentials evoked from C-fibers was higher at longer interstimulus intervals than shorter intervals, thus yielding a negative correlation between the magnitude estimates of the perceived painful sensation and the number of action potentials elicited from nociceptive afferents. This suggests that temporal summation of the nociceptive discharge at central neurons becomes increasingly more important for the sensory discriminative experience of pain evoked by repetitive stimulation. We conclude that human nociceptive C-fibers signal brief noxious mechanical stimuli by the total number of action potentials evoked during a short period of time. However, with repetitive stimulation the total number of action potentials evoked from nociceptors is less important for evoking pain and temporal summation of the nociceptive primary afferent discharge becomes the crucial factor for signaling the magnitude of sensation.

Adult↗
PubMed1993

Conditioning of histamine by bradykinin alters responses of rat nociceptor and human itch sensation.

The effect of a conditioning bradykinin application on histamine induced excitation of cutaneous nociceptors and on histamine induced sensations of volunteers was studied. Using an in vitro skin nerve preparation, unmyelinated polymodal nociceptor units of rats (n = 11) were tested by bathing their receptive fields from the corium side with 10(-5) M solutions of bradykinin and histamine. Following bradykinin superfusion the histamine induced discharges were enhanced, and previously unresponsive units were excited by histamine. Corresponding psychophysical experiments were carried out in 13 healthy volunteers. Histamine iontophoresis (30 mC) induced predominantly itching sensations after an intracutaneous control injection of physiological saline. However, following bradykinin injections (100 microliters of a 10(-7) M solution) histamine induced little itch but rather a burning sensation lasting 1-2 min. Itching remained suppressed even after the burning sensations had subsided. These data support a hypothesis according to which itching is mediated by a sub-population of polymodal nociceptor units, and pain is induced whenever a larger nociceptor population is recruited. In the CNS itch processing is either occluded (masked) by pain processing, or suppressed by inhibitory processes.

Adult↗
PubMed1993

The ability of humans to localise noxious stimuli.

We have investigated the ability of humans to localise noxious stimuli on the dorsum of the hand. Pin-prick (non-penetrating needle prick), noxious heat (round 1 cm2 copper probe heated to 50 degrees C), mustard oil (100% applied topically in a small cotton ball, diameter 5 mm) and histamine (iontophoresis of 20 mC delivered to an area of 75 mm2) were applied to skin with intact innervation and during a differential nerve compression block of the superficial radial nerve when only C-fibres were conducting. The mean mislocalisation (+/- S.E.M.; n = 8) of all stimuli was 9.5 +/- 0.8 mm with normal nerve conduction and 8.9 +/- 1.2 during the differential nerve block. There was no significant difference between the noxious submodalities. By contrast, when nerve conduction was intact, purely tactile stimulation (7 mN von Frey hair) was significantly better localised having a mean error of 5.5 +/- 0.4 mm. We conclude that focal stimuli evoking itch or pain can be localised with high precision which is only marginally worse than for tactile stimuli. This suggests the existence of a somatotopical representation for noxious inputs in the brain similar to that found for tactile stimuli.

Adult↗
PubMed1993

Quantitative assessment of sudomotor activity by capacitance hygrometry.

A commercial capacitive hygrometer device manufactured for use in technical or chemical laboratory environments has been used for quantitative and dynamic assessment of sweat gland activity in selected skin areas. For this purpose the hygrometer device was supplemented by a chamber attached to the skin for collecting evaporated water and a supply of dry nitrogen gas providing a gas flow through the chamber and through the hygrometer capsule. The accuracy of the technique was proven in pilot experiments in which fixed amounts of water were evaporated. A positive correlation was found between the weight of the water and the water evaporation computed from the hygrometer readings (r = 0.997). The time constant of the device was in the range of 10 s. This time constant appears to be fast enough for recording physiological changes in the sweating rate of human subjects. In experiments on healthy subjects sudomotor reflexes were assessed and compared to vasoconstrictor responses and to thermographically measured temperature changes of the skin during the Valsalva manoeuvre and a painful mechanical stimulus. Direct measurement of water evaporation such as by this technique may provide information on sympathetic reactions which could be utilized in both physiological and pathophysiological states.

Absorption↗
PubMed1992

Excitation of cutaneous afferent nerve endings in vitro by a combination of inflammatory mediators and conditioning effect of substance P.

A broad mixture of inflammatory mediators ("inflammatory soup") was used to investigate the responsiveness of primary afferents from rat hairy skin in an in vitro skin-saphenous nerve preparation. In addition, a conditioning effect of the tachykinin substance P on chemosensitivity of nociceptors was examined. Inflammatory soup (IS) was made up in synthetic interstitial fluid from bradykinin, serotonin, histamin and prostaglandin E2 (all 10(-5) M). In addition, the potassium and the hydrogen ion concentration (7 mM, pH 7.0) and the temperature (39.5 degrees C) were elevated. The latter agents, in a control solution, did not excite nociceptors (n = 5). IS was repeatedly superfused over the receptive fields for 5 min at 10 min intervals; substance P (SP 10(-6) and 10(-5) M) was applied during the last 5 min of the interval and during the subsequent IS stimulation. IS excited more than 80% of the mechano-heat sensitive ("polymodal") afferents with slowly conducting nerve fibres (n = 72), but none of the low-threshold mechanoreceptive slow and fast conducting units (n = 17). Slow conducting afferents with high mechanical threshold (n = 35) were weakly, and less frequently (< 20%), driven by IS. A majority, but not all, of the responsive units showed tachyphylaxis upon repeated IS application. None, however, lost its responsiveness completely. Conditioning heat stimulation (32-46.5 degrees C in 20 s) did not enhance the subsequent IS response, which may indicate that sensitizing substances normally released by a noxious heat stimulus were already contained in IS. No sensitization to mechanical (von Frey) or heat stimulation could be established in the period after the IS response had subsided and after the washout was completed, respectively. A short-lived sensitization may have been overlooked under these temporal restrictions. Conditioning SP in 10(-5) M but not in 10(-6) M concentration significantly increased the IS response of polymodal C fibres, by 58% on average (n = 14). SP did not excite the units. Comparing with previous data, we conclude that there is a significant synergism between inflammatory mediators, acting to induce more intense and more sustained discharge via many nociceptors than single mediators alone could achieve. Conditioning substance P can further enhance this algogenic action. Mechanisms of interaction and relative contributions of single substances remain to be elucidated.

Animals↗
PubMed1992

Differential effects of dipyrone, ibuprofen, and paracetamol on experimentally induced pain in man.

In a double-blind cross-over study on 22 healthy subjects the analgesic efficacies of the antipyretic analgesic drugs ibuprofen, dipyrone and paracetamol were tested against placebo using a model of experimentally induced pain. To this purpose interdigital webs were pinched repeatedly for 2 min periods. The painfulness of these stimuli was assessed by the subjects on an electronically controlled visual analogue scale at 10 sec intervals. In addition to the subjective pain ratings the stimulus induced reflex diminution of the blood flow in the stimulated hand was measured with photoplethysmography and laser Doppler flow analysis. The flare response around the stimulated area was assessed with infrared thermography. In this assay system ibuprofen and dipyrone, but not paracetamol, showed statistically significant analgesic effects by preventing hyperalgesia which is normally induced by the repeated stimulation of a skin site. This hypoalgesic effect was not related to the subjective impression of the subjects of the analgesic potency of the respective drug. Sympathetic reflex vasoconstriction was not quantitatively related to the drug induced hypoalgesia. Ibuprofen and, to a minor extent, the other antipyretic analgesic drugs also diminished the stimulus induced flare reaction around the stimulated skin sites.

Acetaminophen↗
PubMed1992

Responsiveness and functional attributes of electrically localized terminals of cutaneous C-fibers in vivo and in vitro.

1. The purpose of the present study was to compare the responsiveness unmyelinated cutaneous units in vivo and in vitro and to determine the proportion of primary afferents innervating the rat hairy skin that do not respond to transient mechanical or thermal stimuli. We have adopted electrical search strategies to locate the terminal arborization of unmyelinated fibers before testing the sensitivity to adequate stimuli. 2. A total of 144 unmyelinated units were studied, of which 31 were obtained from in vivo and 113 from in vitro experiments. 55 afferents were investigated after chronic surgical sympathectomy. Units recorded from sympathectomized rats did not differ in their conduction velocity, electrical thresholds, or receptive properties from units in intact animals. 3. There were only minor differences between the properties of units recorded in vivo and in vitro. This probably reflects technical differences of the setups rather than biological changes introduced by the in vitro conditions. Except for a higher prevalence of mechano-cold sensitive units in vitro, there was no significant difference between the distributions of receptor types. 4. Eight of 31 units (26%) recorded in vivo and 17 of 113 units (15%) obtained from in vitro experiments failed to respond to transient mechanical or thermal stimuli. In vivo, one of eight initially unresponsive units was activated by repeated mechanical and thermal stimulation. Two further units became responsive after topical application of mustard oil. In vitro, 2 of 17 unresponsive units were activated by repeated stimulation. Ten of the remaining unresponsive units were treated with a combination of inflammatory mediators. Four of these units were activated: three developed ongoing activity, and two of them also became responsive to mechanical and/or heat stimuli. The fourth unit responded to probing but was not spontaneously active. 5. We conclude that transient mechanical or thermal stimuli can excite the majority of unmyelinated cutaneous units. However, in vivo and in vitro, part of unmyelinated units are initially unresponsive even to noxious forms of stimulation. Because those unresponsive units were also encountered in sympathectomized preparations, and because some units can be recruited with repeated noxious stimuli or inflammatory agents, it is unlikely that all of them are sympathetic efferents. The same substances that cause sensitization of "normal" nociceptors are capable of recruiting initially unresponsive unmyelinated afferents.

Animals↗
PubMed1992

Protons selectively induce lasting excitation and sensitization to mechanical stimulation of nociceptors in rat skin, in vitro.

In ischemic and in inflamed tissues, pH levels down to 5.4 have been measured, and this local acidosis may contribute to pain and hyperalgesia in disease states. To evaluate the role of acid pH in nociception, we have studied identified primary afferents in a rat skin-saphenous nerve preparation in vitro where the receptive fields can be superfused at the highly permeable corium side with controlled solutions. The nerve endings were exposed to CO2-saturated synthetic interstitial fluid (SIF;pH 6.1) and to carbogen-gassed SIF phosphate buffered to different acid pH levels (5 min duration, 10 min intervals). Mechanical thresholds were repeatedly tested in a "blind" fashion by von Frey hair stimulation. Low-threshold mechanosensitive A beta- (n = 12) and A delta-fibers (n = 11) were not excited or sensitized by acid pH levels. In 24 of 96 nociceptor type C- and A delta-fibers, irregular low-frequency discharge with poor response characteristics was induced. However, a distinct subpopulation of mechanoheat sensitive, "polymodal" C-units (n = 25; 38%) showed stimulus-related responses increasing with proton concentration and encoding the time course of the pH change. Threshold levels were found to range from pH 6.9 to 6.1; mean maximum discharge was at pH 5.2. All such fibers responded to CO2 as well as to phosphate-buffered solution at the same pH 6.1. The CO2 responses, however, displayed significantly shorter latencies and more pronounced dynamic phases. The carboanhydrase blocker acetazolamide markedly delayed and reduced the CO2 responses. Prolonged application of acid pH (30 min) evoked nonadapting activity irrespective of oxygen supply. Many, but certainly not all, fibers sensitive to protons were also driven by capsaicin (10(-6) M, 10(-5) M) and vice versa. Repeated or prolonged treatment with low pH induced a significant and lasting decrease of the mechanical (von Frey) thresholds in almost all C-fibers tested (from 35 to 16 mN, on average), and this occurred whether or not a fiber was excited by protons. The sensitizing effect was more pronounced the higher the initial von Frey thresholds (0.75 rank correlation). This sensitization to mechanical stimulation was in contrast to the combined action of other inflammatory mediators, bradykinin, 5-HT, histamine and prostaglandin E2. In conclusion, we suggest that pH sensitivity of nociceptors may be an important source of pain and hyperalgesia.

Animals↗
PubMed1991

Controlled noxious chemical stimulation: responses of rat trigeminal brainstem neurones to CO2 pulses applied to the nasal mucosa.

The nasal mucosa of halothane-anesthetized rats was stimulated with defined CO2 pulses. Recordings were performed from single trigeminal brainstem neurons to characterize their responses to this controlled chemical irritation. All cells examined with this stimulus displayed graded discharges to increasing concentrations of CO2. Enhanced responses were obtained in a group of neurons when the duration of the interstimulus interval was increased. The application of chemical irritants, notably mustard oil or acetic acid induced vigorous ongoing discharges in all cells tested. The CO2 stimulation method described here thus provides an ideal model for the quantitative physiological and pharmacological examination of chemically induced nociception.

Acetates↗
PubMed1991

Electrophysiological mechanisms in inflammatory pain.

Inflammatory pain is mediated from the periphery by a specialized subgroup of nerve fibers, the nociceptors. The nociceptive nerve endings undergo sensitization and excitation when stimulated with inflammatory agents. It will be shown that a multitude of substances cooperates in this process. Since nociceptive nerve endings are too small to be approached directly with the methods of intracellular electrophysiology, one has to extrapolate to the membrane channels and intracellular processes mediating nociceptor sensitization from studies on the perikarya of sensory ganglion cells. Sustained inflammation induces profound plastic changes in peripheral and central neurones leading to an altered excitability.

Animals↗
PubMed1991

Unresponsive afferent nerve fibres in the sural nerve of the rat.

1. The proportion of primary afferent nerve fibres in a skin nerve of the rat that responded or failed to respond to mechanical or thermal stimulation of the skin in the noxious and non-noxious range was analysed. 2. Activity of afferent nerve fibres was recorded from the dorsal roots. Units projecting into the sural nerve were selected using supramaximal electrical stimulation of the nerve stem. All other hindleg nerves were cut. 3. The receptive fields were searched by carefully examining the hindleg skin with noxious and innocuous mechanical, cooling and warming stimuli. Probing of the intrinsic foot muscles and manipulation of the ankle and toe joints was employed to recruit units projecting to deeper tissues. 4. In a first series of twenty-two experiments, eighty-nine rapidly conducting myelinated A beta units, thirty slowly conducting myelinated A delta units and 101 unmyelinated C units were investigated. Most units were identified as belonging to one of the established classes of cutaneous sensory units and this was also ascertained by a collision test. 5. Two A beta, eight A delta and forty-six C fibres did not respond to any one of the stimuli. Electrical thresholds and conduction velocities of the unresponsive C fibres were not significantly different from those of the units responding to natural stimulation of their receptive fields. In the A delta group unresponsive and high threshold mechanoreceptive units were preferentially found among the units with the slowest conduction velocities. 6. In a second series of seven experiments, one single nerve filament containing responsive and unresponsive C fibres was tested repetitively at 30 min intervals. Twenty unresponsive units and seven units responding to noxious mechanical and/or heat stimuli were studied. Ten of the twenty initially unresponsive units became activated by mechanical and/or heat stimuli after observation times of 30-150 min. Some of these units had mechanical thresholds as low as 64 mN (tested with calibrated von Frey hairs), or thermal thresholds down to 42 degrees C. 7. Two of the ten C units which became responsive in the course of an experiment later lost their responsiveness again. On the other hand, two of the C units which were initially responsive to noxious heat and/or noxious mechanical stimuli became completely unresponsive after repetitive stimulation, whereas one unit initially only responding to noxious heat became responsive to mechanical stimuli, suggesting that mechanical and heat responsiveness may be separately gained or lost by sensory C fibres.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Discharge patterns of human C-fibers induced by itching and burning stimuli.

1. The aim of this investigation was to study the peripheral neural mechanisms of the C-fiber-mediated modalities of burning pain and itch by the use of microneurography of human unmyelinated afferents. 2. Sixteen stable recordings of single C-fibers and 6 multiunit recordings were obtained from the superficial radial nerves of volunteers. All units were excited by stimulating their receptive fields with von Frey bristles (range 10-600 mN), and all but four units were also driven by radiant heat stimulation. 3. Histamine was iontophoretically applied to the receptive fields of these units for 20 or 30 s and was found to provoke itching sensations lasting several minutes, together with wheal and flare responses. Subsequently a solution containing 20 or 30% mustard oil was applied to the receptive field of the respective unit, which provoked a sensation of burning pain. 4. One-half of the units were excited by histamine, and the median discharge rates derived from interspike intervals ranged from approximately 0.1 to 0.8 Hz. Mustard oil-induced activity was observed in all histamine-sensitive units and also in three single units and in one multiunit recording that revealed no histamine response. Median interval-derived discharge rates ranged from 0.2 to 1.2 Hz. 5. Analysis of the interspike interval distribution and of the autocorrelation function derived from the chemically induced discharges of single units provided no evidence for an encoding of itch and burning pain in different discharge patterns of units responding to histamine and to mustard oil.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

[The rating box--a new instrument for ambulatory detection of subjective variables].

For the acquisition of subjective variables in outpatients and inpatients, a new device--the Rating Box--has been designed. The Rating Box provides a standardized, date- and time-logged documentation of symptoms by the patient and rapid transfer of data to a personal computer. The simultaneous acquisition of several symptoms using different types of scales is possible. The acoustic alarm of the Rating Box reminds the patient to enter data at preselected times. The device is easy to handle, even by older patients, and has been successfully tested in the acquisition of pain variables in patients with a variety of painful conditions.

Data Collection↗
PubMed1991

Reactions to intradermally injected substance P and topically applied mustard oil in atopic dermatitis patients.

Skin reactions and itch or burning pain sensations following intradermal injection of the neuropeptide substance P and topical application of the substance P releasing agent mustard oil were studied in 20 atopic dermatitis patients and 20 healthy controls. Changes in skin blood flow were measured with a Laser Doppler flowmeter. Areas of wheal and flare reactions were evaluated planimetrically. Simultaneous with Laser Doppler flowmeter measurements, subjective itch and burning pain ratings were verbally reported on a category partitioning scale at 10-second intervals. Substance P evoked dose-dependent wheal, flare, and itch reactions in both patients and controls. However, substance P doses of 10(-9) -10(-11) mol elicited smaller flares in patients than in the controls whereas the wheal sizes were similar in both groups. Substance P-induced itch ratings were lower in patients at a dose of 10(-10) mol, and the onset of itching was delayed at all substance P levels applied. Mustard oil elicited similar neurogenic inflammatory reactions in both groups, although pain sensations were significantly delayed in atopic dermatitis patients at two mustard oil concentrations, which is further indication of a desensitization of afferent nerve endings contributing to the neurogenic inflammatory reactions in the skin of these patients.

Acute Disease↗
PubMed1991

[Assessment of the effect of ibuprofen and other non-steroidal anti-rheumatic drugs in experimental algesimetry].

This paper describes an experimental method for the assessment of analgesic effects of NSAIDs in healthy human volunteers. Pain was induced by repeated controlled pinching of interdigital webs. The painfulness of the stimulus was assessed by the subjects at regular intervals on an electronically controlled visual analog scale. Furthermore, computer supported infrared thermography, laser Doppler flowmetry and photoplethysmography were used to measure the cutaneous vascular reactions. The results of two double-blind cross-over studies are described in which analgesic effects of acetylsalecylic acid, ibuprofen, and dipyrone were significantly demonstrated. In one of the studies it was also shown that ibuprofen reduced the local stimulus-induced vasodilatation. In summary, this algesimetric model seems to be suited to demonstrate the analgesic and perhaps also the antiinflammatory effects of NSAIDs in healthy subjects.

Arthritis, Rheumatoid↗